WO2008125014A1

WO2008125014A1 - Urea compounds, preparation methods and pharmaceutical uses thereof

Info

Publication number: WO2008125014A1
Application number: PCT/CN2008/000760
Authority: WO
Inventors: Song Li; Xinming Zhou; Wu Zhong; Zhibing Zheng; Junhai Xiao; Lili Wang; Hongying Liu; Yunde Xie
Original assignee: Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A.
Priority date: 2007-04-13
Filing date: 2008-04-14
Publication date: 2008-10-23
Also published as: CN101636397A; CN101636397B

Abstract

The urea compounds of formula I, pharmaceutically acceptable salts and solvates, their preparation methods, the pharmaceutical compositions comprising the said compounds and the uses as p38 kinase inhibitors thereof. The substituents are defined as the description.

Description

脲类化合物，其制备方法及其医药用途技术领域 Urea compound, preparation method thereof and medical use thereof

本发明涉及抑制 P38蛋白激酶的脲类化合物，含有它们的药物組合物，制备这些化合物的方法及它们的医药用途。 The present invention relates to urea compounds which inhibit P38 protein kinase, pharmaceutical compositions containing them, methods for preparing these compounds and their medical use.

背景技术 Background technique

TNF和 IL-1在许多慢性炎症和自身免疫性疾病相关的病理过程中成为核心参与者。 IL-1涉及介导或恶化疾病，如类风湿性关节炎（参见， Arend, W. P. Arthritis&Rheumatism 38(2) ： 151-160, (1995)) ，骨关节炎，骨吸收，中毒性休克综合症，结核病，动脉粥样硬化，糖尿病，何杰金氏病，（参见， Benharroch, D.等. Euro. Cytokine Network 7(1): 51-57)和阿尔茨海默病。已经发现过度或失调的 TNF生产参与介导或恶化疾病，如类风湿性关节炎（（参见， Ma.ini， R. N.等 APMIS. 105(4)： 257-263, (1997); Feldmann, M. , J. of the Royal College of Physicians of London 30(6) ： 560-570, (1996); Lorenz, H. M.等 J. of Immunology 156(4)： 1646-1653, (1996)), 骨关节炎，脊推炎，脓毒症，脓毒性休克（（参见， Abraham, E, 等 JAMA. 277 (19): 1531-1538, (1997),成人呼吸窘迫综合征，哮喘（（参见， Shah, A. 等 .Clin. & Exp. Allergy 1038-1044, (1995) 和 Lassalle, P. 等 Clin. & Exp. Allergy 94 ( 1 ) : 105-110， (1993)) ，骨吸收病，热病（（参见， Cooper, A. L.等 Am. J. of Physiology 267 (6 Pt. 2): 1431-1436)), 脑脊髓炎，脱髓鞘作用（参见， Klindert, W. E.等: Γ. of Neuroimmunol. 72 (2): 163-168，（1997) )和牙周疾病。 TNF and IL-1 are central players in the pathogenesis associated with many chronic inflammation and autoimmune diseases. IL-1 is involved in mediating or worsening diseases such as rheumatoid arthritis (see, Arend, WP Arthritis & Rheumatism 38(2): 151-160, (1995)), osteoarthritis, bone resorption, toxic shock syndrome, Tuberculosis, atherosclerosis, diabetes, Hodgkin's disease, (see, Benharroch, D. et al. Euro. Cytokine Network 7(1): 51-57) and Alzheimer's disease. Excessive or dysregulated TNF production has been found to be involved in mediating or worsening diseases such as rheumatoid arthritis (see, Ma.ini, RN et al. APMIS. 105(4): 257-263, (1997); Feldmann, M. J. of the Royal College of Physicians of London 30(6): 560-570, (1996); Lorenz, HM et al. J. of Immunology 156(4): 1646-1653, (1996)), Osteoarthritis, Spinal inflammatory disease, sepsis, septic shock (see, Abraham, E, et al JAMA. 277 (19): 1531-1538, (1997), adult respiratory distress syndrome, asthma (see, Shah, A. Etc. Clin. & Exp. Allergy 1038-1044, (1995) and Lassalle, P. et al. Clin. & Exp. Allergy 94 (1): 105-110, (1993)), bone resorption, fever (see , Cooper, AL et al. Am. J. of Physiology 267 (6 Pt. 2): 1431-1436)), encephalomyelitis, demyelination (see, Klindert, WE et al: Γ. of Neuroimmunol. 72 (2) : 163-168, (1997)) and periodontal disease.

IL-1和 TNF受体拮抗剂的临床试验显示，阻断这些细胞因子通过其受体发出信号的能力可以在人体中明显改善炎性疾病。所以，这些炎症细胞因子的调控被认为是一种最有效的阻断慢性炎症并具有阳性治疗效果的策略。 Clinical trials of IL-1 and TNF receptor antagonists have shown that blocking the ability of these cytokines to signal through their receptors can significantly ameliorate inflammatory diseases in humans. Place Therefore, regulation of these inflammatory cytokines is considered to be one of the most effective strategies for blocking chronic inflammation with a positive therapeutic effect.

丝裂素激活蛋白激醉（mi togen- act ivated protein Mitogen-activated protein intoxication

kinase, MAPK)级联是细胞内主要信号转导***，细胞外刺激信号通过这一***传递到细胞核，进而导致细胞生长，发育， ***，细胞因子分泌及恶性转化等一系列生理和病理过程。 The kinase, MAPK) cascade is the main signal transduction system in the cell. The extracellular stimulation signal is transmitted to the nucleus through this system, which leads to a series of physiological and pathological processes such as cell growth, development, division, cytokine secretion and malignant transformation.

细胞中大多数蛋白激酶处于非活性状态，当特定的上游激酶信号激活时，导致该激酶发生丝氨酸（seriene，S)，苏氨酸 Most of the protein kinases in the cell are in an inactive state, and when a specific upstream kinase signal is activated, it causes serine (seriene, S), threonine.

(threonine, T)或酪氨酸（tyros ine, Y)残基磷酸化而激活。与其它蛋白激酶不同，所有 MAPK家族成员的活化均需对苏氨酸和酪氨酸残基双位点磷酸化来完成， MAPK双位点磷酸化基团具有 (threonine, T) or tyrosine (y) residues are activated by phosphorylation. Unlike other protein kinases, activation of all MAPK family members requires two-site phosphorylation of threonine and tyrosine residues, and the MAPK double-site phosphorylation group has

Thr-Xaa-Tyr (T-X-Y)的序列特征 (参见 Seger R， Krebs EG. The MAPK s ingal ing cascade. FASEB J. 1995 9: 726-735 ) 。 MAPK的活化和磷酸化通过了包括上游多级激酶在内的级联反应，其中包括三级关键激酶： MAPK, MAPK激酶（MAPK kinase, MAPKK或 Sequence characteristics of Thr-Xaa-Tyr (T-X-Y) (see Seger R, Krebs EG. The MAPK s ingal ing cascade. FASEB J. 1995 9: 726-735). MAPK activation and phosphorylation through a cascade of upstream multi-level kinases, including tertiary kinases: MAPK, MAPK kinase (MAPK kinase, MAPKK or

MEK/MKK) , MAPK激酶激酶（MAPK kinase kinase, MAPKKK)。 MAPKKK 对 MAPKK的丝氨酸，苏氨酸双位点磷酸化而将其激活；活化的 MAPKK 进一步对 MAPK进行丝氨酸，苏氨酸双位点磷酸化而将其激活。（参见 Boul ton T. G. , Nye S. H.， Bobbins D. J.等. Cel l 1991 , 65: 663: 675 ) 。 MEK/MKK), MAPK kinase kinase (MAPKKK). MAPKKK activates the phosphorylation of the serine and threonine sites of MAPKK; the activated MAPKK further activates the MAPK by phosphorylation of the serine and threonine sites. (See Boul ton T. G., Nye S. H., Bobbins D. J. et al. Cel l 1991, 65: 663: 675).

哺乳动物细胞 MAPK 家族至少包括四个亚家族，即 ERK (extracel luar regulated protein kinase) , 皿 (c-Jun N-terminal kinase) , p38 , ERK5。不同亚家族主要通过双磷酸化位点之间的 Xaa和 /或上游激酶的差别来区分。 Mammalian cells The MAPK family includes at least four subfamilies, namely ERK (extracel luar regulated protein kinase), c-Jun N-terminal kinase, p38, ERK5. Different subfamilies are distinguished primarily by differences in Xaa and/or upstream kinase between the phosphorylation sites.

Han等于 1993年首先在内毒素脂多糖（ LPS )刺激后的前 B细胞中发现和克隆了一种 38kDa的 MAPK。 p38 MAPK双磷酸化位点位于笫 180位点和第 182位的酪氨酸和苏氨酸。 p38 MAPK的特异性双碑酸化集团为 Thr-Gly-Tyr。迄今己发现四个 p38 MAPK亚型： ρ38 α ， ρ38 β ， _Ρ38 γ ， ρ3 δ。四种异构体之间约有 60%的同源性，与其它类 Han equalized and found a 38kDa MAPK in the first B cells stimulated by endotoxin lipopolysaccharide (LPS) in 1993. The p38 MAPK double phosphorylation site is located at the 笫180 and 182th tyrosine and threonine. P38 MAPK specific double-acid The group is Thr-Gly-Tyr. Four p38 MAPK subtypes have been identified so far: ρ38 α , ρ38 β , _Ρ 38 γ , ρ3 δ. About 60% homology between the four isomers, with other classes

MAPKs则约有 40-45%的同源性，四种 ρ38的结构中均有一含 TGY三肽模块的环状活性中心，为上游分子的特异性双磷酸化位点。 Ρ38 α， ρ38 β在人体内广泛存在， ρ38 γ主要存在于骨骼肌中， ρ3 δ主要分布于肺，肾，睾丸，胰腺和小肠中。不同亚型的 ρ38在不同的细胞中分布不同。未活化的 ρ38位于胞浆中，活化的 ρ38在胞浆和胞核均可表达。 MAPKs have about 40-45% homology, and all four ρ38 structures have a circular active center containing a TGY tripeptide module, which is a specific double phosphorylation site of the upstream molecule. Ρ38 α, ρ38 β is widely present in the human body. ρ38 γ is mainly found in skeletal muscle, and ρ3 δ is mainly distributed in the lung, kidney, testis, pancreas and small intestine. Different subtypes of ρ38 are distributed differently in different cells. The unactivated ρ38 is located in the cytosol, and the activated ρ38 is expressed in both the cytoplasm and the nucleus.

Lee通过对 ρ38激酶作为一类新的抗炎剂的靶分子的独立发现，提供了 Ρ38激酶参与 LPS—激发的导致促炎性细胞因子生物合成产生的信号传导路径的确切证据 5 [Lee等， Nature, 372, 739 Lee's independent discovery of a target molecule for ρ38 kinase as a new class of anti-inflammatory agents provides definitive evidence that Ρ38 kinase is involved in LPS-stimulated signaling pathways leading to proinflammatory cytokine biosynthesis 5 [Lee et al. Nature, 372, 739

(1994) ] _{o P}38 (Lee将其命名为 CSBP1和 2)的发现提供了一类抗炎化合物的作用机制，其中 SK&F 86002是原型实例。这些化合物在低 μ Μ浓度范围内抑制人单核细胞中 IL- 1和 TNF合成 [Lee等， Int. J. I廳 nopharmac. 10 (7) ， 835 (1988) ]并在动物模型中表现出活性，这些动物模型对环加氧酶抑制剂有抗药性 [Lee等， Annal s N. Y. Acad. Sci. ， 696, 10 149 (1993) ]。现在确信 CSBP/p38是参与应激反应信号传导路径的几种激酶之一其平行于并在很大程度上独立于类似的丝裂素激活蛋白激酶级联。应激反应信号，包括 LPS, 促炎细胞因子，氧化剂， UV线和渗透压，由 CSBP/p38开始激活上游激酶，其依次在苏氛酸 180和酪氨酸 182位点磷酸化 CSBP/p38，导致 CSBP/p38活化。已确定 MAPKAP激酶- 2 , MAPKAP激酶- 3为 (1994)] _{o P} 38 (Lee named it CSBP1 and 2) provides a mechanism for the action of a class of anti-inflammatory compounds, of which SK&F 86002 is a prototype. These compounds inhibit IL-1 and TNF synthesis in human monocytes at low μ Μ concentrations [Lee et al., Int. J. I, nopharmac. 10 (7), 835 (1988)] and show up in animal models. Activity, these animal models are resistant to cyclooxygenase inhibitors [Lee et al, Annal s NY Acad. Sci., 696, 10 149 (1993)]. It is now believed that CSBP/p38 is one of several kinases involved in the stress response signaling pathway that is parallel and largely independent of the similar mitogen-activated protein kinase cascade. Stress response signals, including LPS, pro-inflammatory cytokines, oxidants, UV rays and osmotic pressure, activate the upstream kinase from CSBP/p38, which in turn phosphorylates CSBP/p38 at the sulphonic acid 180 and tyrosine 182 sites. Lead to CSBP/p38 activation. MAPKAP kinase-2 has been identified and MAPKAP kinase-3 is

CSBP/p38的下游底物，其依次磷酸化热激蛋白 Hsp27。已知被 p38 磷酸化的其它下游底物包括激酶 (Mnk 1/2 , MSK1/2和 PRAK)以及转录因子（CHOP , MEF2 , ATF2和 CREB)。虽然需要细胞因子生物合成的很多信号路径尚属未知，但似乎清楚其中涉及很多上述 P38的底物 [Cohen, P. Trends Cel l Biol. , 353 361 (1997)和 Lee, J. C. 等， Pharmacol. Ther. 82： 389-397, ( 1999 ) ]„ 除了抑制 IL-1和 TNF外， p38激酶抑制剂（SK&F86002和 SB 203580)还降低多种促炎蛋白包括 IL-6， IL-8, GM - CSF和 C0X-2的合成。也已表明 CSBP/p38激酶的抑制剂抑制 TNF- ot诱发的 VCAM-1在内皮细胞上的表达， TNF- α诱发的细胞胞质 PLA2的磷酸化和活化以及 IL-1刺激的胶原酶和溶基质素的合成。这些以及其它数据表明 ρ38不仅参与细胞因子的合成，还涉及细胞因子信号【有关 CSBP/P38激酶综述，见 [Cohen, P. Trends Cel l Biol. , A downstream substrate of CSBP/p38, which in turn phosphorylates the heat shock protein Hsp27. Other downstream substrates known to be phosphorylated by p38 include kinases (Mnk 1/2, MSK1/2 and PRAK) and transcription factors (CHOP, MEF2, ATF2 and CREB). Although many of the signal pathways required for cytokine biosynthesis are unknown, it seems clear that many of the above P38 substrates are involved [Cohen, P. Trends Cel l Biol., 353 361 (1997) and Lee, JC). Etc., Pharmacol. Ther. 82: 389-397, (1999) ]„ In addition to inhibiting IL-1 and TNF, p38 kinase inhibitors (SK&F86002 and SB 203580) also reduce a variety of pro-inflammatory proteins including IL-6, IL- 8. Synthesis of GM-CSF and C0X-2 It has also been shown that inhibitors of CSBP/p38 kinase inhibit TNF- ot-induced VCAM-1 expression on endothelial cells, TNF-α-induced phosphorylation of cellular cytoplasmic PLA2 And activation and synthesis of IL-1 stimulated collagenase and stromelysin. These and other data suggest that ρ38 is involved not only in the synthesis of cytokines but also in cytokine signaling [for a review of CSBP/P38 kinases, see [Cohen, P. Trends] Cel l Biol. ,

353-361 (1997) ] 发明内容 353-361 (1997) ] Summary of the invention

本发明的目的是寻找并开发具有 p38 MAPK抑制活性的小分子化合物，用来治疗细胞因子（TNF- o， IL- 1等）介导的疾病，危险因子或病症，如为牛皮癬性关节炎，莱特尔氏综合征，痛风，外伤性关节炎，风疹性关节炎，急性滑膜炎，类风湿性关节炎，类风湿性脊推炎，骨关节炎，痛风性关节炎及其它关节病，败血症，脓毒性休克，内毒素性休克，革兰氏阴性，败血症，中毒性休克综合征，脑型疟，脑膜炎，局部缺血性中风和出血性中风，神经外伤 /闭合性颅脑损伤，哮喘，成人呼吸窘迫综合症，慢性肺炎，慢性阻塞性肺病，矽肺，肺肉瘤病，骨吸收病，骨质疏松，再狹窄，心脏及脑和肾再灌注损伤，充血性心力衰竭，冠状动脉旁路搭桥 (CABG)术，血检形成，肾小球性腎炎，慢性肾衰竭，糖尿病，糖尿病性视网膜病，黄斑变性，移植物抗宿主反应，同种移植物排斥，炎性肠疾病，节段性回肠炎，溃疡性结肠炎神经变性疾病，肌肉退化，糖尿病性视网膜病，黄斑变性，肿瘤生长和转移，血管生成疾病，流感引起的肺炎，湿疹，接触性皮炎，牛皮癣，晒伤或结膜炎等。本发明人已经发现通式 I 的化合物可以用于治疗或预防细胞因子（TNF- a， IL-1等）介导的各种疾病、危险因子或病症。 The object of the present invention is to find and develop a small molecule compound having p38 MAPK inhibitory activity for treating a cytokine (TNF-o, IL-1, etc.) mediated disease, a risk factor or a condition, such as psoriatic arthritis. Lyttle's syndrome, gout, traumatic arthritis, rubella arthritis, acute synovitis, rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, gouty arthritis and other joint diseases, sepsis , septic shock, endotoxic shock, Gram-negative, sepsis, toxic shock syndrome, cerebral malaria, meningitis, ischemic stroke and hemorrhagic stroke, neurological trauma/closed head injury, asthma , adult respiratory distress syndrome, chronic pneumonia, chronic obstructive pulmonary disease, silicosis, pulmonary sarcoma, bone resorption, osteoporosis, restenosis, heart and brain and kidney reperfusion injury, congestive heart failure, coronary artery bypass Bypass (CABG) surgery, blood test formation, glomerulonephritis, chronic renal failure, diabetes, diabetic retinopathy, macular degeneration, Graft versus host response, allograft rejection, inflammatory bowel disease, Crohn's disease, ulcerative colitis neurodegenerative disease, muscle degeneration, diabetic retinopathy, macular degeneration, tumor growth and metastasis, angiogenic diseases , flu-induced pneumonia, eczema, contact dermatitis, psoriasis, sunburn or conjunctivitis. The inventors have found that compounds of formula I are useful in the treatment or prevention of various diseases, risk factors or conditions mediated by cytokines (TNF-a, IL-1, etc.).

因此，在本发明的一个方面，本发明提供通式（I)化合物，或其可药用盐或溶剂化物， Accordingly, in one aspect of the invention, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof,

其中：

among them:

^为^-^。芳香碳环，包括但不限于苯环、取代苯环、环辛四烯、环癸五烯等；或 C ^。饱和或不饱和的非芳香碳环，包括但不限于环戊烷、环己烷、环戊烯、环己烯、环戊二烯、环己二烯等； C₅-d。芳香杂环，包括一到多个选自 0, N, S的杂原子，包括但不限于咪唑、吡唑、吩、唑、喁唑、吡漆、吗啉吡啶、嘧啶、吲哚、吲唑、喹啉等；或者 C₅- C₈的单杂环或者 C₈-Cu的双杂环，包括一到多个选自 0, N, S的杂原子，包括但不限于四氢呋喃、四氢噻吩、哌啶、六氢嘧啶、八氢吲哚等；所述 A 独立并选择性地被一到多个 R₁₅ R₂所取代； ^ is ^-^. Aromatic carbocyclic rings, including but not limited to benzene rings, substituted benzene rings, cyclooctatetraene, cyclopentapentene, etc.; or C ^. A saturated or unsaturated non-aromatic carbocyclic ring including, but not limited to, cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, etc.; C ₅ -d. An aromatic heterocyclic ring, including one or more heteroatoms selected from 0, N, S, including but not limited to imidazole, pyrazole, phenazole, oxazole, oxazole, pyrocoat, morpholine pyridine, pyrimidine, hydrazine, carbazole and quinoline; or a C ₅ - C ₈ heteromonocyclic or C ₈ -Cu double heterocycle, comprising one or more heteroatoms selected from 0, N, S heteroatoms, including but not limited to tetrahydrofuran, tetrahydrothiophene , piperidine, hexahydropyrimidine, octahydropurine, etc.; said A is independently and optionally substituted by one to more R ₁₅ R ₂ ;

Ar₂为苯并五元或六元杂环。当为五元杂环时，环上包括 1-3 个选自 0， N, S的杂原子，包括但不限于苯并呋喃、苯并噻吩、苯并吡咯、苯并吡唑、苯并二氢呋喃、苯并二氢噻吩、苯并二氢吡咯、苯并二氢吡唑、苯并噻唑、苯并二氢噻唑等；当为六元杂环时，环上有一个选自 0, S的杂原子或 2-4个选自 0， N, S的杂原子，包括但不限于苯并吡喃、苯并噻喃、苯并嘧啶、苯并喁嗪、苯并二氢吡喃、苯并二氢噻喃、苯并哌啶、苯并二氢噻臻、苯并吗啉等；所述 Ar₂可选择性地被 1-4个选自下面的取代基取代：（^-0!₆直链或支链烷基， C₂- C₆直链或支链烯基， d-C₆直链或支链烷氧基， C广 C₆直链或支链烯氧基，三氟甲基，三氟甲氧基，乙酰基，芳酰基，卤素，甲氧羰基，乙氧羰基，苯磺酰基，羟基，氨基，单或双(^- C₄烷基取代的氨基，单或双 d-O^基取代的氨基磺酰基，腈基，硝基，氨基磺酰基； Ar ₂ is a benzo five- or six-membered heterocyclic ring. When it is a five-membered heterocyclic ring, the ring includes 1-3 heteroatoms selected from 0, N, S, including but not limited to benzofuran, benzothiophene, benzopyrrole, benzopyrazole, benzodiazepine Hydrofuran, benzodihydrothiophene, benzodihydropyrrole, benzodihydropyrazole, benzothiazole, benzodihydrothiazole, etc.; when it is a six-membered heterocyclic ring, one ring is selected from 0, S Heteroatoms or 2-4 heteroatoms selected from 0, N, S, including but not limited to benzopyran, benzothiopyran, benzopyrimidine, benzoxazine, benzo Dihydropyran, benzoin, benzopiperidin, benzodihydrothiazide, benzomorpholine, etc.; said Ar ₂ may be optionally substituted with from 1 to 4 substituents selected from the group consisting of : (^-0! ₆ straight or branched alkyl, C ₂ - C ₆ straight or branched alkenyl, dC ₆ straight or branched alkoxy, C broad C ₆ straight or branched olefin , trifluoromethyl, trifluoromethoxy, acetyl, aroyl, halogen, methoxycarbonyl, ethoxycarbonyl, phenylsulfonyl, hydroxy, amino, mono or bis(^-C ₄ alkyl substituted amino a mono- or bi-dO^-substituted aminosulfonyl group, a nitrile group, a nitro group, an aminosulfonyl group;

L独立的为 L independent

( 2 ) C广 (^饱和或不饱和的，直链或支链碳链；其中的一到多个亚甲基独立且选择性被 0， NH, S ( 0 ) _ra或者 0-2个漿基所替代；并且所述联接基团可选择性被一到多个卤原子取代； (2) C-rich (saturated or unsaturated, linear or branched carbon chain; one or more methylene groups independently and selectively 0, NH, S ( 0 ) _ra or 0-2 pulp Substituting; and the linking group is optionally substituted with one or more halogen atoms;

m为 0， 1或 2; m is 0, 1 or 2;

P为苯基，萘基，喹啉基，异喹啉基，吡啶基，嘧啶基，哒嗪基，咪唑基，喁唑基，异喁唑基，噻唑基，异噻唑基，吡咯基，苯并咪唑基，呋喃基，噻吩基，吡喃基，萘啶基，哌嗪基，吡唑基，噻唑基，嘌呤基，吡唑并 [ 3， 4-b]嘧啶基，吡咯并 [2 , 3 - b〗吡啶基，吡咯并 [3, 4- b]吡啶基， 1， 3-氧氮杂并 [4， 5- b]吡啶基， 1 , 2 , 3-三氮唑基， 1， 2， 4-三氮唑基，四氮唑基，四氢吡喃基，四氢呋喃基，二氢萘基，四氢萘基，二氢喹啉基，四氢喹啉基，二氢异喹啉基，四氢异喹啉基， 1 , 3-二氧环戊酮基， 1， 3-二氧环己酮基， 1， 4-二氧六环基，吗啉基，硫代吗啉基，亚砜代吗啉基，砜代吗啉基，哌啶基，哌啶酮基，哌啶醇基，四氢嘧啶酮基，环己酮基，环己醇基，硫杂己环基，五亚甲基亚砜基，五亚甲基砜基，四氢噻吩基，四亚甲基亚砜基，四亚甲基砜基；所述基团可任选被 1-3个选自下面的取代基取代： d-Cs直链或支链烷基， C₂-C₆直链或支链烯基， C₆直链或支链烷氧基， C₂-C₆直链或支链烯氧基，三氟甲基，三氟甲氧基，乙酰基，芳酰基，卤素，苯磺酰基，羟基，氨基，单或双 Cr" C₄烷基取代的氨基，单或双 (^- 烷基取代的氨基酰基， C C^烷氧藏基， d- 酰氧基，单或双 C广 C₄烷基取代的氨基磺酰基，腈基，硝基，氨基磺酰基； P is phenyl, naphthyl, quinolyl, isoquinolinyl, pyridyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, benzene Imidazolyl, furyl, thienyl, pyranyl, naphthyridyl, piperazinyl, pyrazolyl, thiazolyl, fluorenyl, pyrazolo[3,4-b]pyrimidinyl, pyrrolo[2, 3 - b pyridine, pyrrolo[3,4- b]pyridinyl, 1, 3-oxathia[4,5-pyridinyl, 1, 2, 3-triazolyl, 1, 2,4-triazolyl, tetrazolyl, tetrahydropyranyl, tetrahydrofuranyl, dihydronaphthyl, tetrahydronaphthyl, dihydroquinolyl, tetrahydroquinolyl, dihydroisoquinoline , tetrahydroisoquinolyl, 1, 3-dioxocyclopentanone, 1, 3-dioxocyclohexanone, 1, 4-dioxocyclo, morpholinyl, thiomorpholinyl , sulfoxide morpholino, sulfonylmorpholinyl, piperidinyl, piperidinone, piperidinyl, tetrahydropyrimidinone, cyclohexanone, cyclohexanol, thiacyclohexyl, Pentamethylsulfoxide, pentamethylenesulfone, tetrahydrothiophenyl , a tetramethylene sulfoxide group, a tetramethylene sulfone group; the group may be optionally substituted with from 1 to 3 substituents selected from the group consisting of: d-Cs straight or branched alkyl, C ₂ - C ₆ straight or branched alkenyl, C ₆ straight or branched alkoxy, C ₂ -C ₆ straight or branched Alkenyloxy, trifluoromethyl, trifluoromethoxy, acetyl, aroyl, halogen, benzenesulfonyl, hydroxy, amino, mono or double Cr" C ₄ alkyl substituted amino, mono or double (^- Alkyl-substituted aminoacyl, CC^alkoxy, d-acyloxy, mono or di-C-C ₄ alkyl substituted aminosulfonyl, nitrile, nitro, aminosulfonyl;

R¹独立的为 R ^{1 is} independent

( 1 ) d- 。直链或支链烷基，所述烷基可部分或全部被卤代，并且可选择性被 1-3个苯基，萘基或以下的杂环取代：喹啉基，异喹啉基，吡啶基，嘧啶基，哒嗪基，哌嗪基，吡咯基，咪唑基，吡唑基，呋喃基，噻吩基，异喁唑基，异噻唑基；上述苯基，萘基或杂环可被 0-5个下述基团取代：鹵素， d-C^直链或支链坑基， C₃-C₃环烷基， C₅ C_s环烯基，羟基，腈基， d-Ce直链或支链烷氧基，三氟甲基，三氟甲氧基，氨基羰基，双 (^-(^烷基取代的氨基羰基；(1) d-. a linear or branched alkyl group which may be partially or fully halogenated and optionally substituted with from 1 to 3 phenyl, naphthyl or a heterocyclic ring: quinolyl, isoquinolinyl, Pyridyl, pyrimidinyl, pyridazinyl, piperazinyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, isoxazolyl, isothiazolyl; the above phenyl, naphthyl or heterocyclic ring can be 0-5 of the following group substitutions: halogen, dC^ straight or branched chain, C ₃ -C ₃ cycloalkyl, C ₅ C _s cycloalkenyl, hydroxy, nitrile, d-Ce straight or Branched alkoxy, trifluoromethyl, trifluoromethoxy, aminocarbonyl, bis(^-(^alkyl substituted aminocarbonyl;

( 2 ) CrC!。环烷基或环烯基，所迷基团可部分或全部被卤代，或选择性被 1- 3个 C广 C₆焼基或 (广^烷氧基取代；上述的环烷基或环烯基的 1-3个亚甲基可选择性被 0， NH, S, SO, S0₂，羰基，羟甲基替代；上述环烷基或环烯基可独立的被 0-5个以下基团取代：卤素， C₆直链或支链焼基， OC₆直链或支链烷氧基； (2) CrC!. a cycloalkyl or cycloalkenyl group, the group may be partially or fully halogenated, or optionally substituted by 1 to 3 C-C ₆ fluorenyl or (a wide alkoxy group; the above-mentioned cycloalkyl or ring) The 1-3 methylene groups of the alkenyl group may be optionally substituted by 0, NH, S, SO, S0 ₂ , carbonyl, hydroxymethyl; the above cycloalkyl or cycloalkenyl group may be independently 0-5 or less Substituted: halogen, C ₆ straight or branched fluorenyl, OC ₆ straight or branched alkoxy;

( 3 ) ( · 。直链或支链烯基，所迷烷基可部分或全部被卤代，并且可选择性被 1-3个 d-Oi直链或支链烷基，苯基，萘基或以下的杂环取代：喹啉基，异喹啉基，吡啶基，嘧啶基，哒嗪基，哌嗪基，吡咯基，咪唑基，吡唑基，呋喃基，噻吩基，异喁唑基，异噻唑基；上述苯基，萘基或杂环可被 0-5个下迷基团取代：卤素， C广 C₆直链或支链烷基，。环烷基， 0₅-( ₈环烯基，羟基，腈基，直链或支链垸氧基，三氟甲基，三氟甲氧基，氨基叛基，双 (^-( ₄烷基取代的氨基羰基； (3) ( · · linear or branched alkenyl group, the alkyl group may be partially or fully halogenated, and may be optionally 1-3 d-Oi linear or branched alkyl, phenyl, naphthalene Substituted or substituted heterocyclic ring: quinolyl, isoquinolinyl, pyridyl, pyrimidinyl, pyridazinyl, piperazinyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, isoxazole Alkyl, isothiazolyl; the above phenyl, naphthyl or heterocyclic ring may be substituted by 0-5 groups: halogen, C wide C ₆ straight or branched alkyl, cycloalkyl, 0 ₅ - ( _8- cycloalkenyl, hydroxy, nitrile, linear or branched decyloxy, trifluoromethyl, trifluoromethoxy, amino-reactive, bis-( _4- alkyl substituted aminocarbonyl;

( 4 ) 卤素，硝基，羧基，羟基，腈基，三氟甲基，三氟甲氧基； (5) NH-, R³NH -， R³ ₂N-, R³NCO-R³CONH -， R³C00-， R³0C0-， R³S (0) _ra, R³S (0) _mNH, R³NHS(0)_B- ； (4) halogen, nitro, carboxy, hydroxy, nitrile, trifluoromethyl, trifluoromethoxy; (5) NH-, R ³ NH -, R ³ ₂ N-, R ³ NCO-R ³ CONH -, R ³ C00-, R ³ 0C0-, R ³ S (0) _ra , R ³ S (0) _m NH, R ³ NHS(0) _B - ;

R²独立的为 R ² independent is

(1) 芳环，芳杂环基或稠合芳环，包括苯基，萘基，喹啉基，异喹啉基，吡啶基，嘧啶基，哒嗪基，咪唑基，喁唑基，异喁唑基，噻唑基，异噻唑基，吡咯基，呋喃基，噻吩基，吡喃基，萘啶基，哌嗪基，吡唑基，噻唑基，嘌呤基，吲哚基，苯并咪唑基，苯并呋喃基，苯并吡唑基，苯并噻吩基，苯并喁唑基，苯并异噁唑基，苯并噻唑基，苯并异噻唑基，吡唑并 [3, 4-b]嘧啶基，吡咯并 [2， 3-b]吡啶基，吡咯并 [3， 4-b]吡啶基， 1， 3-氧氮杂并 [4, 5- b]吡啶基， 1, 2， 3-三氮唑基， 1, 2， 4-三氮唑基，四氮唑基，四氢吡喃基，四氢呋喃基，二氢萘基，四氢蔡基，二氢喹啉基，四氢喹啉基，二氢异喹啉基，四氢异喹啉基，苯并环丁基，茚基，茚烯基。上述芳环，芳杂环或稠合芳环基可独立的被 0-5 个 R⁴基团取代； (1) aromatic ring, aromatic heterocyclic or fused aromatic ring, including phenyl, naphthyl, quinolyl, isoquinolinyl, pyridyl, pyrimidinyl, pyridazinyl, imidazolyl, carbazolyl, iso Carbazolyl, thiazolyl, isothiazolyl, pyrrolyl, furyl, thienyl, pyranyl, naphthyridyl, piperazinyl, pyrazolyl, thiazolyl, fluorenyl, fluorenyl, benzimidazolyl , benzofuranyl, benzopyrazolyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, pyrazolo[3, 4-b Pyrimidinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, 1, 3-oxathia[4,5-pyridinyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, tetrazolyl, tetrahydropyranyl, tetrahydrofuranyl, dihydronaphthyl, tetrahydrocainyl, dihydroquinolinyl, tetrahydrogen Quinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, benzocyclobutyl, decyl, nonenyl. The above aromatic ring, aromatic heterocyclic ring or fused aromatic ring group may be independently substituted by 0-5 R ⁴ groups;

(2) ( - 。环烷基或环烯基，所迷基团可部分或全部被卤代，或选择性被 1-3个 d-C₆烷基或 d- C₆烷氧基取代； (2) (-.cycloalkyl or cycloalkenyl, the group may be partially or fully halogenated, or optionally substituted by 1-3 dC ₆ alkyl or d-C ₆ alkoxy;

(3) d-C^。直链或支链烷基，所述烷基可部分或全部被卤代； (3) d-C^. a linear or branched alkyl group which may be partially or fully halogenated;

(4) NH₂-, R³NH -， R³ ₂N -， R³NCO-R³CONH -， R³C00 -， R³0C0-， R³S(0)_n， R³S (0) _mNH, R³NHS (0) - ； (4) NH ₂ -, R ³ NH -, R ³ ₂ N -, R ³ NCO-R ³ CONH -, R ³ C00 -, R ³ 0C0-, R ³ S(0) _n , R ³ S (0 _m NH, R ³ NHS (0) - ;

R³独立的为 R ³ independent is

氢原子，直链或支链焼基， d-C₆直链或支链烯基，苯基，萘基，单或双 d- C₄烷基氨基 C广 C₆烷基； m为 0， 1或 2; a hydrogen atom, a linear or branched fluorenyl group, a dC ₆ straight or branched alkenyl group, a phenyl group, a naphthyl group, a mono or a double d-C ₄ alkylamino C C ₆ alkyl group; m is 0, 1 or 2;

R⁴独立的为 R ⁴ independent is

a) 卤素，硝基，羧基， d- 直链或支链烷基， d-C₆直链或支链烯基， C₃- 。环烷基， C₅- (₈环烯基，羟基，腈基， d-C₆直链或支链烷氧基，三氟甲基，三氟甲氧基； a) halogen, nitro, carboxy, d-linear or branched alkyl, dC ₆ straight or branched alkenyl, C ₃ - . Cycloalkyl, C ₅ - ( ₈ cycloalkenyl, hydroxy, nitrile, dC ₆ straight chain or Branched alkoxy, trifluoromethyl, trifluoromethoxy;

b) ΝΗ₂-, R³NH -， R³ ₂N -， R³NC0-R³CONH-, R³COO-₅ R³0C0-, R³S (0) _ra， R³S (0) _fflNH， R³NHS (0) - 。 b) ΝΗ ₂ -, R ³ NH -, R ³ ₂ N -, R ³ NC0-R ³ CONH-, R ³ COO- ₅ R ³ 0C0-, R ³ S (0) _ra , R ³ S (0) _Ffl NH, R ³ NHS (0) - .

另一方面，本发明提供包含本发明通式（I)化合物的药用组合物，其含有至少一种通式（I)化合物或其可药用盐、溶剂化物，以及一种或多种药用载体或赋形剂。 In another aspect, the invention provides a pharmaceutical composition comprising a compound of formula (I) according to the invention, which comprises at least one compound of formula (I), or a pharmaceutically acceptable salt, solvate thereof, and one or more Use a carrier or excipient.

另一方面，本发明还涉及制备通式（I)化合物或者其可药用盐或溶剂化物的方法。 In another aspect, the invention relates to a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

再一方面，本发明涉及通式（I)化合物用于制备治疗和 /或预防细胞因子（TNF- ct， IL-1等）介导的疾病或病症的药物的用途。 In a further aspect, the invention relates to the use of a compound of formula (I) for the manufacture of a medicament for the treatment and/or prevention of a cytokine (TNF-ct, IL-1, etc.) mediated disease or condition.

在又一方面，本发明提供了治疗和 /或预防细胞因子（TNF- a , IL-1等）介导的疾病、危险因子或病症的方法，包括给予有此需要的对象治疗和 /或预防有效量的本发明化合物。本发明中所述的细胞因子（TNF- ot， IL-1等）介导的疾病、危险因子或病症包括牛皮癣性关节炎，莱特尔氏综合征，痛风，外伤性关节炎，风疹性关节炎，急性滑膜炎，类风湿性关节炎，类风湿性脊推炎，骨关节炎，痛风性关节炎及其它关节病，败血症，脓毒性休克，内毒素性休克，革兰氏阴性，败血症，中毒性休克综合征，脑型疟，脑膜炎，局部缺血性中风和出血性中风，神经外伤 /闭合性颅脑损伤，哮喘，成人呼吸窘迫综合症，慢性肺炎，慢性阻塞性肺病，矽肺，肺肉瘤病，骨吸收病，骨质疏松，再狭窄，心脏及脑和肾再濯注损伤，充血性心力衰竭，冠状动脉旁路搭桥（CABG)术，血检形成，肾小球性肾炎，慢性肾衰竭，糖尿病，糖尿病性视网膜病，黄斑变性，移植物抗宿主反应，同种移植物排斥，炎性肠疾病，节段性回肠炎，溃疡性结肠炎神经变性疾病，肌肉退化，糖尿病性视网膜病，黄斑变性，肿瘤生长和转移，血管生成疾病，流感引起的肺炎，湿疹，接触性皮炎，牛皮癣，晒伤或结膜炎等。 In yet another aspect, the invention provides methods of treating and/or preventing a cytokine (TNF-a, IL-1, etc.) mediated disease, risk factor or disorder, comprising administering to a subject in need thereof treatment and/or prevention An effective amount of a compound of the invention. The cytokine (TNF- ot, IL-1, etc.) mediated diseases, risk factors or conditions described in the present invention include psoriatic arthritis, Lyttle's syndrome, gout, traumatic arthritis, rubella arthritis , acute synovitis, rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, gouty arthritis and other joint diseases, sepsis, septic shock, endotoxic shock, Gram-negative, sepsis, Toxic shock syndrome, cerebral malaria, meningitis, ischemic stroke and hemorrhagic stroke, neurological trauma/closed craniocerebral injury, asthma, adult respiratory distress syndrome, chronic pneumonia, chronic obstructive pulmonary disease, silicosis, Pulmonary sarcoma, bone resorption, osteoporosis, restenosis, heart and brain and kidney re-inflation injury, congestive heart failure, coronary artery bypass grafting (CABG), blood test, glomerulonephritis, Chronic renal failure, Diabetes, Diabetic retinopathy, Macular degeneration, Graft-versus-host response, Allograft rejection, Inflammatory bowel disease, Segmental Ileitis, ulcerative colitis, neurodegenerative diseases, muscle degeneration, diabetic retinopathy, macular degeneration, tumor growth and metastasis, angiogenic diseases, flu-induced pneumonia, eczema, contact dermatitis, Psoriasis, sunburn or conjunctivitis.

在本发明的一个实施方式中，本发明提供了通式 I化合物、其可药用盐或溶剂化物， In one embodiment of the invention, the invention provides a compound of formula I, a pharmaceutically acceptable salt or solvate thereof,

I I

其中： among them:

为^-^。芳香碳环，包括但不限于苯环、取代苯环、环争四烯、环癸五烯等；或^- 饱和或不饱和的非芳香碳环，包括但不限于环戊烷、环己烷、环戊烯、环己烯、环戊二烯、环己二烯等； Is ^-^. Aromatic carbocyclic ring, including but not limited to benzene ring, substituted benzene ring, cyclotetraene, cyclopentaene, etc.; or ^- saturated or unsaturated non-aromatic carbocyclic ring, including but not limited to cyclopentane, cyclohexane , cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, etc.;

G-d。芳香杂环，包括一到多个选自 0， N, S的杂原子，包括但不限于咪唑、吡唑、蓉哈、？ :唑、喁唑、吡療、吗啉吡啶、嘧啶、吲哚、吲唑、喹啉等；或者 C₅-C₈的单杂环或者 Cs-Cu的双杂环，包括一到多个选自 0， N, S的杂原子，包括但不限于四氢呋喃、四氢噻吩、哌啶、六氢嘧啶、八氢吲哚等；所述 Ar!独立并选择性地被一到多个， 11₂所取代； Gd. Aromatic heterocycles, including one or more heteroatoms selected from 0, N, S, including but not limited to imidazole, pyrazole, rongha, ? : azole, carbazole, pyrotherapy, morpholine pyridine, pyrimidine, hydrazine, oxazole, quinoline, etc.; or C ₅ -C ₈ monoheterocycle or Cs-Cu diheterocycle, including one or more Heteroatoms from 0, N, S, including but not limited to tetrahydrofuran, tetrahydrothiophene, piperidine, hexahydropyrimidine, octahydropurine, etc.; said Ar! independently and selectively one to more, 11 ₂ Replaced

Ar₂为苯并五元或六元杂环。当为五元杂环时，环上包括 1-3 个选自 0， N, S的杂原子，包括但不限于苯并呋喃、苯并噻吩、苯并吡咯、苯并吡唑、苯并二氢呋喃、苯并二氢噻吩、苯并二氢吡咯、苯并二氢吡唑、苯并噻唑、苯并二氢噻唑等；当为六元杂环时，环上有一个选自 0 , S的杂原子或 2- 4个选自 0， N, S的杂原子，凶、包括但不限于苯并吡喃、苯并噻喃、苯并嘧啶、苯并嗪、苯并二氢吡喃、苯并二氢噻喃、苯并哌啶、苯并二氢噻嗪、苯并吗啉等；所述 Ar₂可选择性地被 1-4个选自下面的取代基取代： d-Cs 直链或支链垸基， C₂-C₆直链或支链烯基， d-C₆直链或支链烷氧基， C₂ - C₆直链或支链烯氧基，三氟甲基，三氟甲氧基，乙酰基，芳酰基，卤素，甲氧羰基，乙氧叛基，苯磺酰基，羟基，氨基，单或双(^- C₄烷基取代的氨基，单或双 d- 烷基取代的氨基磺酰基，腈基，硝基，氨基磺酰基； Ar ₂ is a benzo five- or six-membered heterocyclic ring. When it is a five-membered heterocyclic ring, the ring includes 1-3 heteroatoms selected from 0, N, S, including but not limited to benzofuran, benzothiophene, benzopyrrole, benzopyrazole, benzodiazepine Hydrofuran, benzodihydrothiophene, benzodihydropyrrole, benzodihydropyrazole, benzothiazole, benzodihydrothiazole, etc.; when it is a six-membered heterocyclic ring, one ring selected from 0, S Heteroatoms or 2 to 4 heteroatoms selected from 0, N, S, including but not limited to benzopyran, benzothiopyran, benzopyrimidine, benzoxazine, chroman, Benzohydropyran, benzopiperidine, benzodihydrothiazide, benzo Morpholine or the like; the Ar ₂ may be optionally substituted with from 1 to 4 substituents selected from the group consisting of: d-Cs straight or branched fluorenyl, C ₂ -C ₆ straight or branched alkenyl, dC ₆ straight or branched alkoxy, C ₂ - C ₆ straight or branched alkenyloxy, trifluoromethyl, trifluoromethoxy, acetyl, aroyl, halogen, methoxycarbonyl, ethoxylated Base, phenylsulfonyl, hydroxy, amino, mono or bis (^-C ₄ alkyl substituted amino, mono or di d-alkyl substituted aminosulfonyl, nitrile, nitro, sulfamoyl;

L独立的为 L independent

( 2 ) ^-^。饱和或不饱和的，直链或支链碳链；其中的一到多个亚曱基独立的被 0， NH, S ( 0 ) _a或者 0-2个叛基所替代；并且所述联接基团可被一到多个卤原子取代； (2) ^-^. a saturated or unsaturated, linear or branched carbon chain; wherein one or more of the fluorenylene groups are independently replaced by 0, NH, S ( 0 ) _a or 0-2 thiol; and the linking group The group may be substituted by one or more halogen atoms;

m为 0， 1或 2j m is 0, 1 or 2j

P为苯基，萘基，喹啉基，异喹啉基，吡啶基，嘧啶基，哒嗪基，咪唑基，喁唑基，异喁唑基，噻唑基，异噻唑基，吡咯基，苯并咪唑基，呋喃基，噻吩基，吡喃基，萘啶基，哌嗪基，吡唑基，噻唑基，嘌呤基，吡唑并 [3， 4-b]嘧啶基，吡咯并 [2， 3 - b] 吡啶基，吡咯并 [3， 4-b]吡啶基， 1， 3-氧氮杂并 [4 , 5-b]吡啶基， 1 , 2， 3-三氮唑基， 1 , 2， 4-三氮唑基，四氮唑基，四氢吡喃基，四氢呋喃基，二氢萘基，四氢萘基，二氢喹啉基，四氢喹啉基，二氢异喹啉基，四氢异喹啉基， 1， 3-二氧环戊酮基， 1， 3-二氧环己酮基， 1， 4-二氧六环基，吗啉基，硫代吗啉基，亚砜代吗啉基，砜代吗啉基，哌啶基，哌啶酮基，哌啶醇基，四氢嘧啶酮基，环己酮基，环己醇基，硫杂己环基，五亚甲基亚砜基，五亚甲基砜基，四氢噻吩基，四亚甲基亚砜基，四亚甲基砜基；所述基团可任选被 1-3个选自下面的取代基取代： d- C₆直链或支链烷基， C₂-C_fi直链或支链烯基， C广 C_fi直链或支链烷氧基， C₂-C₆直链或支链烯氧基，三氟甲基，三氟甲氧基，乙酰基，芳酰基，卤素，苯磺酰基，羟基，氨基，单或双烷基取代的氨基，单或双 d-C₄烷基取代的氨基酰基， Cr^烷氧羰基， d-C₅酰氧基，单或双 (^-^烷基取代的氨基磺酰基，腈基，硝基，氨基磺酰基； P is phenyl, naphthyl, quinolyl, isoquinolinyl, pyridyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, benzene Imidazolyl, furyl, thienyl, pyranyl, naphthyridyl, piperazinyl, pyrazolyl, thiazolyl, fluorenyl, pyrazolo[3,4-b]pyrimidinyl, pyrrolo[2, 3 - b] pyridyl, pyrrolo[3,4-b]pyridyl, 1, 3-oxathia[4,5-pyridinyl, 1, 2, 3-triazolyl, 1 , 2,4-triazolyl, tetrazolyl, tetrahydropyranyl, tetrahydrofuranyl, dihydronaphthyl, tetrahydronaphthyl, dihydroquinolyl, tetrahydroquinolyl, dihydroisoquinoline , tetrahydroisoquinolyl, 1, 3-dioxocyclopentanone, 1, 3-dioxocyclohexanone, 1, 4-dioxolyl, morpholinyl, thiomorpholinyl , sulfoxide morpholino, sulfonylmorpholinyl, piperidinyl, piperidinone, piperidinyl, tetrahydropyrimidinone, cyclohexanone, cyclohexanol, thiacyclohexyl, Pentamethylsulfoxide, pentamethylenesulfone, tetrahydrothiophenyl Group tetramethylene sulfoxide, tetramethylene sulfone group; the group may be optionally substituted with 1-3 substituents selected from: d- C ₆ linear or branched alkyl, C ₂ - C _fi straight or branched alkenyl, C wide C _fi straight or branched alkoxy, C ₂ -C ₆ straight or branched alkenyloxy, trifluoromethyl, trifluoromethoxy, acetyl , aroyl, halogen, benzenesulfonate Acyl, hydroxy, amino, mono or dialkyl substituted amino, mono or di dC ₄ alkyl substituted amino, Cr^ alkoxycarbonyl, dC ₅ acyloxy, mono or bis(^-^alkyl substituted Aminosulfonyl, nitrile, nitro, aminosulfonyl;

R¹独立的为 R ^{1 is} independent

( 1 ) d- 。直链或支链烷基，所迷烷基可部分或全部被卤代，并且可被 1-3个苯基，萘基或以下的杂环取代：喹啉基，异喹啉基，吡啶基，嘧啶基，哒嗪基，哌嗪基，吡咯基，咪唑基，吡唑基，呋喃基，噻哈基，异噍唑基，异噻唑基；上述苯基，茶基或杂环可被 0-5个下述基团取代：！¾素， d-C^直链或支链烷基， C₃-C₃环烷基，（^- 环烯基，羟基，腈基，直链或支链烷氧基，三氟甲基，三氟甲氧基，氨基羰基，双 ( ^烷基取代的氨基漿基；(1) d-. A straight or branched alkyl group, the alkyl group may be partially or fully halogenated, and may be substituted by 1-3 phenyl, naphthyl or a heterocyclic ring: quinolyl, isoquinolinyl, pyridyl , pyrimidinyl, pyridazinyl, piperazinyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, thiahaki, isoxazolyl, isothiazolyl; the above phenyl, tea or heterocyclic ring can be 0 - 5 of the following groups replaced: ! 3⁄4, dC^ straight or branched alkyl, C ₃ -C ₃ cycloalkyl, (^-cycloalkenyl, hydroxy, nitrile, linear or branched alkoxy, trifluoromethyl, trifluoro Methoxy, aminocarbonyl, bis(^alkyl substituted amino syrup;

( 2 ) C₃- 。环烷基或环烯基，所迷基团可部分或全部被卤代，或被 1-3个 C广 C₆烷基或 Cr-C₆烷氧基取代；上述的环烷基或环烯基的 1-3个亚甲基可被 0, NH, S， SO, S0₂, 羰基，羟甲基替代；上述环烷基或环烯基可独立的被 0-5个以下基团取代：卤素，直链或支链貌基， d-Cs直链或支链烷氧基； (2) C ₃ - . a cycloalkyl or cycloalkenyl group, the group may be partially or fully halogenated, or substituted by 1-3 C-C ₆ alkyl or Cr-C ₆ alkoxy; the above cycloalkyl or cycloalkenyl The 1-3 methylene groups of the group may be replaced by 0, NH, S, SO, S0 ₂ , carbonyl, hydroxymethyl; the above cycloalkyl or cycloalkenyl group may be independently substituted by 0-5 groups: Halogen, straight or branched chain base, d-Cs straight or branched alkoxy;

( 3 ) C₃- 。直链或支链烯基，所述烷基可部分或全部被卤代，并且可被 1-3个(^- C₆直链或支链烷基，苯基，萘基或以下的杂环取代：喹啉基，异喹啉基，吡啶基，嘧啶基，哒嗪基，哌嗪基，吡咯基，咪唑基，吡唑基，呋喃基，噻吩基，异嚙唑基，异噻唑基；上述苯基，萘基或杂环可被 0-5个下述基团取代：鹵素， d-C₆ 直链或支链烷基， C₃- 。环烷基， - 环烯基，羟基，腈基， d-C₆ 直链或支链烷氧基，三氟甲基，三氟甲氧基，氨基羰基， ^C -C₄ 烷基取代的氨基羰基； (3) C ₃ - . a linear or branched alkenyl group which may be partially or fully halogenated, and may be substituted by 1 to 3 (^-C ₆ linear or branched alkyl, phenyl, naphthyl or the following heterocyclic ring) Substituents: quinolyl, isoquinolinyl, pyridyl, pyrimidinyl, pyridazinyl, piperazinyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, isoxazolyl, isothiazolyl; The above phenyl, naphthyl or heterocyclic ring may be substituted by 0-5 groups: halogen, dC ₆ straight or branched alkyl, C ₃ - cycloalkyl, -cycloalkenyl, hydroxy, nitrile , dC ₆ straight or branched alkoxy, trifluoromethyl, trifluoromethoxy, aminocarbonyl, ^C -C ₄ alkyl substituted aminocarbonyl;

( 4 ) 卤素，硝基，羧基，羟基，腈基，三氟甲基，三氟甲氧基； (4) halogen, nitro, carboxy, hydroxy, nitrile, trifluoromethyl, trifluoromethoxy;

( 5 ) NH₂-, R³NH -， R³ ₂N -， R³NCO-R³CONH-, R³C00-， R³0C0—， R³S (0) _ra， R³S (0) _nNH, R³NHS (0) _a- ； ( 5 ) NH ₂ -, R ³ NH -, R ³ ₂ N -, R ³ NCO-R ³ CONH-, R ³ C00-, R ³ 0C0—, R ³ S (0) _ra , R ³ S (0) _n NH, R ³ NHS (0) _a - ;

R²独立的为 R ² independent is

( 1 ) 苯环，芳杂环基或稠合芳环，包括苯基，萘基，喹淋基，异喹啉基，吡啶基，嘧啶基，哒嗪基，咪唑基，喁唑基，异嚙唑基，噻唑基，异噻唑基，吡咯基，呋喃基，噻吩基，吡喃基，茶啶基，哌嗪基，吡唑基，噻唑基，嘌呤基，吲哚基，苯并咪唑基，苯并呋喃基，苯并吡唑基，苯并噻吩基，苯并喁唑基，苯并异喁唑基，苯并噻唾基，苯并异噻唑基，吡唑并 [3， 4- b]嘧啶基，吡咯并 [2 , 3-b]吡啶基，吡咯并 [3， 4- b]吡啶基， 1， 3-氧氮杂并 (1) phenyl ring, aromatic heterocyclic or fused aromatic ring, including phenyl, naphthyl, quinolyl, isoquinolinyl, pyridyl, pyrimidinyl, pyridazinyl, imidazolyl, carbazolyl, iso Olezolyl, thiazolyl, isothiazolyl, pyrrolyl, furyl, thienyl, pyranyl, phylyridyl, piperazinyl, pyrazolyl, thiazolyl, fluorenyl, fluorenyl, benzimidazolyl , benzofuranyl, benzopyrazolyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzothiazino, benzisothiazolyl, pyrazolo[3, 4- b]pyrimidinyl, pyrrolo[2,3-b]pyridyl, pyrrolo[3,4-b]pyridyl, 1, 3-oxaza

[4， 5- b]吡啶基， 1， 2， 3-三氮唑基， 1， 2， 4-三氮唑基，四氮唑基，四氢吡喃基，四氢呋喃基，二氢萘基，四氢萘基，二氢喹啉基，四氢喹啉基，二氢异喹啉基，四氢异喹啉基，苯并环丁基，茚基，茚烯基。上述芳环，芳杂环或稠合芳环基可独立的被 0-5 个 R⁴基团取代； [4, 5- b]pyridyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, tetrazolyl, tetrahydropyranyl, tetrahydrofuranyl, dihydronaphthyl , tetrahydronaphthyl, dihydroquinolyl, tetrahydroquinolyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, benzocyclobutyl, decyl, nonenyl. The above aromatic ring, aromatic heterocyclic ring or fused aromatic ring group may be independently substituted by 0-5 R ⁴ groups;

( 2 ) C₃- 。环烷基或环烯基，所述基团可部分或全部被卤代，或被 1-3个 C广 C₆烷基或 d-C₆烷氧基取代； (2) C ₃ - . a cycloalkyl or cycloalkenyl group, the group may be partially or fully halogenated, or substituted with 1-3 C-C ₆ alkyl or dC ₆ alkoxy;

( 3 ) d- 。直链或支链烷基，所述烷基可部分或全部被卤代； (3) d-. a linear or branched alkyl group which may be partially or fully halogenated;

( 4 ) NH₂-, R³NH -， R³ ₂N -， R³NCO-R CONH-, R³C00-, R³0C0-, R³S (0) _m, R³S (0) _fflNH, R³NHS (0) - ； (4) NH ₂ -, R ³ NH -, R ³ ₂ N -, R ³ NCO-R CONH-, R ³ C00-, R ³ 0C0-, R ³ S (0) _m , R ³ S (0) _Ffl NH, R ³ NHS (0) - ;

R³独立的为 R ³ independent is

氢原子， d- C₆直链或支链烷基， CrC_fi直链或支链烯基，苯基，萘基，单或双 C₄烷基氨基(^-(^烷基； m为 0， 1或 2; Hydrogen atom, d-C ₆ straight or branched alkyl group, CrC _fi straight or branched alkenyl group, phenyl, naphthyl group, mono or di C ₄ alkylamino group (^-(^ alkyl; m is 0 , 1 or 2;

R⁴独立的为 R ⁴ independent is

a) 卤素，硝基，羧基， C广 C₆直链或支链烷基，（^- 直链或支链烯基， CfC!。环烷基， -(：₈环烯基，羟基，腈基， d- C₆直链或支链烷氧基，三氟甲基，三氟甲氧基； b) 冊广， R³NH-, R³ ₂N-, R³NCO-R³CONH-, R³C00 -， R³0C0 -， R³S (0) _m， R³S (0) _mNH, R³NHS (0) _m- ； a) halogen, nitro, carboxy, C-C ₆ straight or branched alkyl, (^- straight or branched alkenyl, CfC!. cycloalkyl, -(: ₈ cycloalkenyl, hydroxy, nitrile , d-C ₆ straight or branched alkoxy, trifluoromethyl, trifluoromethoxy; b) Wide range, R ³ NH-, R ³ ₂ N-, R ³ NCO-R ³ CONH-, R ³ C00 -, R ³ 0C0 -, R ³ S (0) _m , R ³ S (0) _m NH, R ³ NHS (0) _m - ;

在本发明的一个优选实施方式中，本发明提供了通式 I 所代表的化合物，其可药用盐或溶剂化物， In a preferred embodiment of the invention, the invention provides a compound represented by formula I, a pharmaceutically acceptable salt or solvate thereof,

I I

其中： among them:

^为 -^。芳香碳环，包括但不限于苯环、取代苯环、环辛四烯、环癸五烯等，' 或。饱和或不饱和的非芳香碳环，包括但不限于环戊烷、环己烷、环戊烯、环己烯、环戊二烯、环己二烯等； ^ is -^. Aromatic carbocyclic rings, including but not limited to benzene rings, substituted benzene rings, cyclooctatetraene, cyclopentaene, etc., or . a saturated or unsaturated non-aromatic carbocyclic ring, including but not limited to cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, etc.;

C₅-C_1Q芳香杂环，包括一到多个选自 0， N， S的杂原子，包括但不限于咪唑、吡唑、噻吩、噻唑、喁唑、吡嚓、吗啉吡啶、嘧啶、吲哚、吲唑、喹啉等；或者 C广 c_s的单杂环或者 c₈- c_u的双杂环，包括一到多个选自 0, N, S的杂原子，包括但不限于四氢呋喃、四氢噻吩、哌啶、六氢嘧啶、八氢吲哚等；所述 A 独立并选择性地被一到多个 R₂所取代； a C ₅ -C _1Q aromatic heterocycle comprising one or more heteroatoms selected from 0, N, S, including but not limited to imidazole, pyrazole, thiophene, thiazole, oxazole, pyridinium, morpholinium pyridine, pyrimidine, An oxime, a carbazole, a quinoline or the like; or a monoheterocyclic ring of C-C _s or a bi-heterocyclic ring of c ₈ - c _u , including one or more heteroatoms selected from 0, N, S, including but not limited to Tetrahydrofuran, tetrahydrothiophene, piperidine, hexahydropyrimidine, octahydropurine, etc.; said A is independently and selectively substituted by one to more R ₂ ;

Ar₂为苯并吡喃或苯并二氢吡喃基；所述 Ar₂可被 1-4个选自下面的取代基取代： C「C₆直链或支链烷基， C₂- C₆直链或支链烯基， d-C₆直链或支链烷氧基， C₂-C₆直链或支链烯氧基，三氟甲基，三氟甲氧基，乙酰基，芳酰基，卤素，甲氧叛基，乙氧羰基，苯磺酰基，羟基，氨基，单或双 d C^烷基取代的氨基，单或双 (广^烷基取代的氨基磺酰基，腈基，硝基，氨基磺酰基； Ar ₂ is a benzopyran or a chromanyl group; the Ar ₂ may be substituted with from 1 to 4 substituents selected from C: C ₆ straight or branched alkyl, C ₂ - C ₆ straight or branched alkenyl, dC ₆ straight or branched alkoxy, C ₂ -C ₆ straight or branched alkenyloxy, trifluoromethyl, trifluoromethoxy, acetyl, aroyl , halogen, methoxyhistyl, ethoxycarbonyl, phenylsulfonyl, hydroxy, amino, mono- or di-d-C-alkyl substituted amino, mono- or bi- Substituted aminosulfonyl, nitrile, nitro, aminosulfonyl;

L独立的为 L independent

( 1 )键； (1) key;

( 2 ) ( ^。饱和或不饱和的，直链或支链碳链；其中的一到多个亚甲基独立的被 0， ΝΗ, S ( 0 ) _m或者 0-2个裁基所替代；并且所迷联接基团可被一到多个卤原子取代； ( 2 ) ( ^. Saturated or unsaturated, linear or branched carbon chain; one or more methylene groups independently replaced by 0, ΝΗ, S ( 0 ) _m or 0-2 And the linking group can be substituted by one or more halogen atoms;

m为 0, 1或 2; m is 0, 1 or 2;

P为苯基，萘基，喹啉基，异喹啉基，吡啶基，嘧啶基，哒嗪基，咪唑基，喁唑基，异喁唑基，噻唑基，异噻唑基，吡咯基，苯并咪唑基，呋喃基，噻吩基，吡喃基，萘啶基，哌嗪基，吡唑基，噻唑基，嘌呤基，吡唑并 [3， 4- b]嘧啶基，吡咯并 [2 , 3-b] 吡啶基，吡咯并 [3 , 4- b]吡啶基， 1 , 3-氧氮杂并 [4， 5-b]吡啶基， 1， 2 , 3-三氮唑基， 1， 2， 4-三氮唑基，四氮唑基，四氢吡喃基，四氢呋喃基，二氢萘基，四氢萘基，二氢喹啉基，四氢喹啉基，二氢异喹啉基，四氢异喹啉基， 1 , 3-二氧环戊酮基， 1， 3-二氧环己酮基， 1 , 4-二氧六环基，吗啉基，硫代吗啉基，亚砜代吗啉基，砜代吗啉基，哌啶基，哌啶酮基，哌啶醇基，四氢嘧啶酮基，环己酮基，环己醇基，硫杂己环基，五亚甲基亚砜基，五亚甲基砜基，四氢噻吩基，四亚甲基亚砜基，四亚甲基砜基；所述基团可任选被 1-3个选自下面的取代基取代: 直链或支链垸基， C₂- C₆直链或支链烯基， d- 直链或支链烷氧基， C₂-C₆直链或支链烯氧基，三氟甲基，三氟甲氧基，乙酰基，芳酰基，卤素，苯磺酰基，羟基，氨基，单或双 C广 C₄烷基取代的氨基，单或双 d-C₄烷基取代的氨基酰基，（广 ₄烷氧羰基， d-Cs酰氧基，单或双 d- C₄烷基取代的氨基磺酰基，腈基，硝基，氨基磺酰基； P is phenyl, naphthyl, quinolyl, isoquinolinyl, pyridyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, benzene Imidazolyl, furyl, thienyl, pyranyl, naphthyridyl, piperazinyl, pyrazolyl, thiazolyl, fluorenyl, pyrazolo[3,4-b]pyrimidinyl, pyrrolo[2, 3-b] pyridyl, pyrrolo[3,4-b]pyridinyl, 1, 3-oxaza-[4,5-pyridinyl, 1, 2, 3-triazolyl, 1, 2,4-triazolyl, tetrazolyl, tetrahydropyranyl, tetrahydrofuranyl, dihydronaphthyl, tetrahydronaphthyl, dihydroquinolyl, tetrahydroquinolyl, dihydroisoquinoline , tetrahydroisoquinolyl, 1, 3-dioxocyclopentanone, 1, 3-dioxocyclohexanone, 1,4-dioxolyl, morpholinyl, thiomorpholinyl , sulfoxide morpholino, sulfonylmorpholinyl, piperidinyl, piperidinone, piperidinyl, tetrahydropyrimidinone, cyclohexanone, cyclohexanol, thiacyclohexyl, Pentamethylsulfoxide, pentamethylsulfone, tetrahydrothiophenyl, Sulfoxide group, tetramethylene sulfone group; the group may be optionally substituted with 1-3 substituents selected from: a straight-chain or branched-chain alkyl, C ₂ - C ₆ linear or Branched alkenyl, d-linear or branched alkoxy, C ₂ -C ₆ straight or branched alkenyloxy, trifluoromethyl, trifluoromethoxy, acetyl, aroyl, halogen, benzene Sulfonyl, hydroxy, amino, mono or di C C ₄ alkyl substituted amino, mono or di dC ₄ alkyl substituted amino acyl, (a wide ₄ alkoxycarbonyl, d-Cs acyloxy, single or double d - a C ₄ alkyl substituted aminosulfonyl group, a nitrile group, a nitro group, an aminosulfonyl group;

R¹独立的为 R ^{1 is} independent

( 1 ) d- 。直链或支链烷基，所述烷基可部分或全部被卤代，并且可被 1-3个苯基，萘基或以下的杂环取代：喹啉基，异喹啉基，吡啶基，嘧啶基，哒嚓基，哌嗪基，吡咯基，咪唑基，吡唑基，呋喃基，噻吩基，异嚙唑基，异噻唑基；上述苯基，萘基或杂环可被 0-5个下述基团取代：卤素， CrC₆直链或支链烷基， (^- 环烷基， C₅- 环烯基，羟基，腈基， d-Cs直链或支链烷氧基，三氟甲基，三氟甲氧基，氨基羰基，双 (广烷基取代的氨基羰基；(1) d-. a linear or branched alkyl group, the alkyl group may be partially or wholly halogenated And substituted by 1-3 phenyl, naphthyl or a heterocyclic ring: quinolyl, isoquinolinyl, pyridyl, pyrimidinyl, fluorenyl, piperazinyl, pyrrolyl, imidazolyl, Pyrazolyl, furyl, thienyl, isotazolyl, isothiazolyl; the above phenyl, naphthyl or heterocyclic ring may be substituted by 0-5 groups: halogen, CrC ₆ straight or branched alkane , (^-cycloalkyl, C ₅ -cycloalkenyl, hydroxy, nitrile, d-Cs straight or branched alkoxy, trifluoromethyl, trifluoromethoxy, aminocarbonyl, bis (wide) Alkyl substituted aminocarbonyl;

( 2 ) C厂 d。环烷基或环烯基，所述基团可部分或全部被鹵代，或被 1- 3个 d- C₆烷基或 d-Ce烷氧基取代；上述的环烷基或环烯基的卜 3个亚甲基可被 0， NH, S, SO, S0₂，羰基，羟甲基替代；上述环烷基或环烯基可独立的被 0-5个以下基团取代：卤素， d-Cs 直链或支链烷基， d- C₆直链或支链烷氧基； (2) C factory d. a cycloalkyl or cycloalkenyl group, said group being partially or fully halogenated, or substituted by 1 to 3 d-C ₆ alkyl or d-Ce alkoxy; above cycloalkyl or cycloalkenyl The 3 methylene groups may be replaced by 0, NH, S, SO, S0 ₂ , carbonyl, hydroxymethyl; the above cycloalkyl or cycloalkenyl may be independently substituted by 0-5 groups: halogen, d-Cs straight or branched alkyl, d-C ₆ straight or branched alkoxy;

( 3 ) C₃- 。直链或支链烯基，所述烷基可部分或全部被卤代，并且可被 1-3个(^- C₆直链或支链烷基，苯基，萘基或以下的杂环取代：喹啉基，异喹啉基，吡啶基，嘧啶基，哒嗪基，哌嗪基，吡咯基，咪唑基，吡唑基，呋喃基，噻吩基，异喵唑基，异噻唑基；上述苯基，萘基或杂环可被 0-5个下迷基团取代：卤素， d-C₆ 直链或支链烷基， C₃- 。环烷基， 0₅-( ₈环烯基，羟基，腈基， CrCe 直链或支链烷氧基，三氟甲基，三氟甲氧基，氨基羰基，双 C广 C₄ 垸基取代的氨基羰基； (3) C ₃ - . a linear or branched alkenyl group which may be partially or fully halogenated, and may be substituted by 1 to 3 (^-C ₆ linear or branched alkyl, phenyl, naphthyl or the following heterocyclic ring) Substituents: quinolyl, isoquinolinyl, pyridyl, pyrimidinyl, pyridazinyl, piperazinyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, isoxazolyl, isothiazolyl; The above phenyl, naphthyl or heterocyclic ring may be substituted by 0-5 groups: halogen, dC ₆ straight or branched alkyl, C ₃ - cycloalkyl, 0 ₅ -( ₈ cycloalkenyl, a hydroxy group, a nitrile group, a CrCe linear or branched alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, an aminocarbonyl group, a bis-C-C ₄ fluorenyl-substituted aminocarbonyl group;

( 5 ) NH₂—， R³NH -， R³ ₂N -， R³NCO-R³CONH-, R³C00 -， R³0C0 -， R³S (0) _m, R³S (0) M, R³NHS (0) - ； (5) NH ₂ —, R ³ NH -, R ³ ₂ N -, R ³ NCO-R ³ CONH-, R ³ C00 -, R ³ 0C0 -, R ³ S (0) _m , R ³ S (0 M, R ³ NHS (0) - ;

R²独立的为 R ² independent is

( 1 ) 环，芳杂环基或稠合芳环，包括苯基，萘基，喹啉基，异喹啉基，吡啶基，嘧啶基，哒嗪基，咪唑基，喁唑基，异喁唑基，噻唑基，异噻唑基，吡洛基，呋喃基，噻喻基，吡喃基，蔡啶基，哌嗪基，吡唑基，噻唑基，嘌呤基，吲哚基，苯并咪唑基, 苯并呋喃基，苯并吡唑基，苯并噻吩基，苯并喁嗤基，苯并异喁唑基，苯并噻唑基，苯并异噻唑基，吡唑并 [3, 4-b]嘧啶基，吡咯并 [2 , 3- b]吡啶基，吡咯并 [3 , 4- b]吡啶基， 1， 3-氧氮杂并 [4 , 5-b]吡啶基， 1 , 2， 3-三氮唑基， 1 , 2 , 4-三氮唑基，四氮唑基, 四氢吡喃基，四氢呋喃基，二氢萘基，四氢萘基，二氢喹啉基，四氢喹啉基，二氢异喹啉基，四氢异喹啉基，苯并环丁基，茚基，茚烯基。上述芳环，芳杂环或稠合芳环基可独立的被 0-5个 R⁴基团取代； (1) a ring, an aromatic heterocyclic group or a fused aromatic ring, including phenyl, naphthyl, quinolyl, isoquinolinyl, pyridyl, pyrimidinyl, pyridazinyl, imidazolyl, carbazolyl, isoindole Azyl, thiazolyl, isothiazolyl, pyrrolyl, furyl, thiol, pyranyl, ca Pyridyl, piperazinyl, pyrazolyl, thiazolyl, fluorenyl, fluorenyl, benzimidazolyl, benzofuranyl, benzopyrazolyl, benzothienyl, benzindenyl, benzo Isoxazolyl, benzothiazolyl, benzisothiazolyl, pyrazolo[3,4-b]pyrimidinyl, pyrrolo[2,3-b]pyridyl, pyrrolo[3,4-b] Pyridyl, 1, 3-oxathia[4,5-pyridinyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, tetrazolyl, tetrahydrogen Pyranyl, tetrahydrofuranyl, dihydronaphthyl, tetrahydronaphthyl, dihydroquinolyl, tetrahydroquinolyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, benzocyclobutyl, anthracene Base, decyl. The above aromatic ring, aromatic heterocyclic ring or fused aromatic ring group may be independently substituted by 0-5 R ⁴ groups;

( 2 ) C₃- C_le环烷基或环烯基，所述基团可部分或全部被卤代，或被 1-3个(^-(^烷基或 d- C₆烷氧基取代； (2) C ₃ -C _le cycloalkyl or cycloalkenyl, said group may be partially or fully halogenated, or substituted by 1-3 (^-(^ alkyl or d-C ₆ alkoxy) ;

( 4 ) NH₂-, R³NH-， R³ ₂N -， R³NC0— R³C0NH -， R³C00 -， R³0C0-， R³S (0) _m， R³S (0) _mNH, R³NHS (0) - ； (4) NH ₂ -, R ³ NH-, R ³ ₂ N -, R ³ NC0 - R ³ C0NH -, R ³ C00 -, R ³ 0C0-, R ³ S (0) _m , R ³ S (0 _m NH, R ³ NHS (0) - ;

R³独立的为 R ³ independent is

氢原子， Ci-Cs直链或支链烷基， d-Ce直链或支链烯基，苯基, 萘基，单或双 d-C₄烷基氨基 d-C₆烷基； m为 0， 1或 2; a hydrogen atom, a straight or branched alkyl group of Ci-Cs, a linear or branched alkenyl group of d-Ce, a phenyl group, a naphthyl group, a mono or double dC ₄ alkylamino dC ₆ alkyl group; m is 0, 1 or 2;

R⁴独立的为 R ⁴ independent is

a) 卤素，硝基，羧基， d-C₆直链或支链坑基， Cr 直链或支链烯基， C₃- C_1D环烷基， C₅- (：₈环烯基，羟基，腈基， d- c₆直链或支链烷氧基，三氟甲基，三氟甲氧基； a) halogen, nitro, carboxy, dC ₆ straight or branched chain, Cr straight or branched alkenyl, C ₃ - C _1D cycloalkyl, C ₅ - (: ₈ cycloalkenyl, hydroxy, nitrile Base, d-c ₆ straight or branched alkoxy, trifluoromethyl, trifluoromethoxy;

b) NH广， R³NH -， R³ ₂N -， R³NCO-R³CONH-, R³C00- , R³0C0 -， R³S (0) _ffi, R³S (0) _mNH, R³NHS (0) - ； b) NH wide, R ³ NH -, R ³ ₂ N -, R ³ NCO-R ³ CONH-, R ³ C00- , R ³ 0C0 -, R ³ S (0) _ffi , R ³ S (0) _m NH, R ³ NHS (0) - ;

本发明优选的化合物包括： Preferred compounds of the invention include:

1- [ 3 -叔丁基- 1 -（4-甲基苯基） -1H-5 -吡唑基〗 -3- [8- (3, 4 二氢 -5-甲氧基 -2^ "色烯基) ]脲 1- [3-叔丁基 -1- (4-氯苯基) -1^"5-吡唑基] -3- [8- (5-甲氧基1-[ 3 -tert-butyl- 1 -(4-methylphenyl) -1H-5 -pyrazolyl-3-(8-(3,4 dihydro-5-methoxy-2^" Alkenyl) 1-[3-tert-Butyl-1-(4-chlorophenyl)-1^"5-pyrazolyl]-3-[8-(5-methoxy

- 2^色烯基）]脲 - 2^color alkenyl)]urea

1 - [3 -叔丁基 -1 -（4-甲基苯基) - 1H - 5-吡唑基] -3- [8- (5-甲氧基- 2 色烯基) ]脲 1-[3-tert-butyl-l-(4-methylphenyl)-1H-5pyrazolyl]-3-[8-(5-methoxy-2-chromenyl)]urea

1- [3-叔丁基 -1- (4-甲基苯基） - 1H-5-吡唑基] -3- {5- {8- [2- (⁴-***啉基）乙酰氨基] -²^色烯基 } }脲 1-[3-tert-Butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{5-{8- [2-( ⁴ -morpholinyl)acetamido] - ² ^色烯}}Urea

卜 [3-叔丁基 -1-苯基 -1^5-吡唑基 ] -3- [8- (3 , 4-二氢 -5 -甲氧基 -2^"色烯基) ]脲 [3-tert-Butyl-1-phenyl-1^5-pyrazolyl]-3-[8-(3,4-dihydro-5-methoxy-2^"chromenyl)]urea

1- [ 3-叔丁基 -1- (4-甲基苯基) - 1H - 5 -吡唑基] -3 - {8- {3， 4 -二氢 -5- [2- (4-***啉基）乙氧基] -2^·色烯基 } }脲 1- [ 3-tert-Butyl-1-(4-methylphenyl) - 1H - 5 -pyrazolyl] -3 - {8- {3, 4 - dihydro-5- [2- (4- Morpholinyl)ethoxy] -2^·chromenyl} }urea

1 - [3-叔丁基- 1- (4-甲基苯基） -1H-5-吡唑基] -3- [8- (5-硝基 1-[3-tert-butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-[8-(5-nitro

- ² 色烯基）]脲 - ^2- color alkenyl)]urea

1 - [ 3-叔丁基 -1-苯基 -1^5-吡唑基] -3- {8- {3 , 4-二氢 -5- [2- (4-***啉基）乙氧基] -2^色烯基 Π脲 1-[3-tert-Butyl-1-phenyl-1^5-pyrazolyl]-3-{8- {3,4-dihydro-5-[2-(4-morphinolinyl)ethoxylate -2^-alkenyl guanidinium

1 -〖3-叔丁基 -1- (4-氟苯基） -1^-5-吡唑基] -3- {8- {3 , 4-二氢 - ⁵-〖²- (4-***啉基）乙氧基] -²^"色烯基 } }脲 1 - [3-tert-butyl-1-(4-fluorophenyl)-1^-5-pyrazolyl]-3-{8- {3 , 4-dihydro- ⁵ - [ ² - (4- Morpholinyl)ethoxy] - ² ^"alkenyl}}urea

1- [ 3-叔丁基 -1 (4-氯苯基） -1^-5-吡唑基] -3- {8- {3, 4-二氢 -5 - [2- (4-***啉基）乙氧基] 色烯基 } }脲 1-[ 3-tert-butyl-1(4-chlorophenyl)-1^-5-pyrazolyl]-3-{8- {3, 4-dihydro-5-[2-(4-morphine) Phenyl)ethoxy]chromenyl}}urea

1 - [ 3-叔丁基 -1- (4-溴苯基) ~1^5-吡唑基] -3- {8- {3， 4-二氢 -5- [2- (4-***啉基）乙氧基] - 2 色烯基脲 1-[3-tert-Butyl-1-(4-bromophenyl)~1^5-pyrazolyl]-3-{8- {3, 4-dihydro-5-[2-(4-morphine) Phenyl)ethoxy]-2 alkenyl urea

1 - [ 3-叔丁基 -1 -（4-甲氧基苯基) -l 5-吡唑基] -3- {8- {3, 4- 二氢 -5- [2- (4-***啉基）乙氧基] -² 色烯基 } }脲 1-[3-tert-Butyl-1 -(4-methoxyphenyl)-l 5-pyrazolyl]-3-{8- {3, 4-dihydro-5- [2- (4- Morpholine) ethoxy] - ² color alkenyl} } urea

1- [3-叔丁基 - 1- (4-氨基磺酰基苯基）- 吡唑基] -3- {8- {3， 4 -二氢 -5- [2- (4-***啉基）乙氧基〗色烯基 } } 脲 1-[3-tert-butyl-1-(4-aminosulfonylphenyl)-pyrazolyl]-3-{8- {3,4-dihydro-5-[2-(4-morphinolinyl) Ethoxyl alkenyl} } urea

1- [3-叔丁基-1- (4-硝基苯基） -1^"5-吡唑基] -3- {8- {3， 4 -二氢- 5- [2- (4-***啉基）乙氧基] -2^色烯基 } }脲 [3-叔丁基 : L- (4-甲基苯基) - 1H-5 -吡唑基] -3- {8- [3， 4 二氢一 ₅- (4-***啉基酰基甲氧基) -2 色烯基] }脲 1-[3-tert-Butyl-1-(4-nitrophenyl)-1^"5-pyrazolyl]-3-{8- {3, 4-dihydro-5-[2- (4 - morphinolinyl)ethoxy] -2^-alkenyl}}urea [3-tert-butyl: L-(4-methylphenyl)-1H-5-pyrazolyl]-3-{8- [3, 4 dihydro- _5- (4-morphinolinyl methoxyl) Base) -2 color alkenyl] } urea

1- (3-叔丁基 -5-异喁唑基） -3- {8- {3， 4-二氢 - 5- [2- (4-*** 啉基）乙氧基] - 2^色烯基 } }脲 1-(3-tert-butyl-5-isoxazolyl)-3-{8- {3,4-dihydro-5-[2-(4-morphinolinyl)ethoxy]-2^ Alkenyl}

1- (5-叔丁基 -3-异喁唑基） -3- {8- {3， 4-二氢 -5- [2- (4-*** 啉基）乙氧基] - 2 色烯基 } }脲 1-(5-tert-Butyl-3-isoxazolyl)-3-{8- {3,4-dihydro-5-[2-(4-morphinolinyl)ethoxy]-2-chromene Urea

1- [1-叔丁基 -3- (4-甲基苯基) -1^4 -吡唑基] -3- {8- {3， 4 -二氢 -5- [2- (4-***啉基）乙氧基] 色烯基 } }脲 1- [1-tert-Butyl-3-(4-methylphenyl)-1^4-pyrazolyl]-3-{8- {3, 4-dihydro-5- [2- (4- Morpholinyl)ethoxy]chromenyl}}urea

1- [4-叔丁基 -卜（4-甲基苯基) -1^2-咪唑基] -3- {8- {3, 4-二氢- 5- [2- (4-***啉基）乙氧基] - 色烯基 } }脲 1-[4-tert-Butyl-bu(4-methylphenyl)-1(2-imidazolyl)-3-(8-{3,4-dihydro-5-[2-(4-morpholine) Ethyl]-chromenyl} }urea

1- [3-叔丁基- 1- (4 -甲基苯基) - 1H-5-吡唑基] -3- {8- {3， 4-二氢 -5- [2- (4-吡啶基）氧基乙氧基] -2^~色烯基 } }脲 1-[3-tert-butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{8- {3, 4-dihydro-5- [2- (4- Pyridyl)oxyethoxy] -2^~chromenyl} }urea

1- [3-叔丁基 -1- (4-甲基苯基) - 1H-5-吡唑基] - 3- {8- {3 , 4-二氲 -5 - {2- [4- (顺式 - 2， 6-二甲基） ***啉基]乙氧基 } - ² ^色烯基 "脲 1-[3-tert-Butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3--{8- {3, 4-diindole-5 - {2- [4- (cis-2,6-dimethyl)morphinolinyl]ethoxy} ^-2 ^-alkenyl "urea

1-〖3-叔丁基 -1- (4-甲基苯基) -1H-5 -吡唑基] -3- {8- {3， 4 -二氢 -5- [2- (1-咪唑基）乙氧基] - 2 色烯基 } }脲 1-〖3-tert-Butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{8- {3, 4-dihydro-5- [2- (1- Imidazolyl)ethoxy]-2 alkenyl}}urea

1- [3-叔丁基 -1- (4-甲基苯基) -1H-5-吡唑基] -3- {8- {3, 4 -二氢- 5- [2- (1-1， 2， 4-三氮唑基）乙氧基] 色烯基 } }脲 1-[3-tert-Butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{8- {3, 4-dihydro-5-[2-(1- 1, 2, 4-triazolyl)ethoxy]chromenyl}}urea

1 - [3-叔丁基- 1-（4-氯苯基) -1^"5-吡唑基] -3- {8- {3， 4-二氢 - 5- {2- [4- (顺式 -2， 6-二甲基）***啉基]乙氧基 } - 2^·色烯基 } } 脲 1-[3-tert-butyl-1-(4-chlorophenyl)-1^"5-pyrazolyl]-3-{8- {3, 4-dihydro- 5- {2- [4- (cis-2,6-dimethyl)morphinolinyl]ethoxy} - 2^·chromenyl} } Urea

1- [3-叔丁基 -1- (3， 4 -二甲基苯基) -I 5 -吡唑基] -3- {8 - {3， 4 -二氢 -5- [2- (4-***啉基）乙氧基] - 2^·色烯基 } }脲 1-[3-tert-Butyl-1-(3,4-dimethylphenyl)-I5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-( 4-morphocolinyl)ethoxy] - 2^·chromenyl} }urea

1- [3-叔丁基 -1- (3， 4-二氯苯基) - l 5-吡唑基] -3- {8- {3 , 4 -二氢 -5- [2- (⁴-***啉基）乙氧基〗 -²^"色烯基 } }脲 1-[3-tert-Butyl-1-(3,4-dichlorophenyl)-l 5-pyrazolyl]-3-{8- {3 , 4 -dihydro-5- [2- ( ⁴ -morpholinyl)ethoxy] - ² ^"alkenyl}}urea

1- [3-叔丁基 - 1- (3-甲基苯基） -1^5 -吡唑基] -3- {8- {3， 4 -二氢 -5- [2- (4-***啉基）乙氧基] ² 色烯基 } }脲 1-[3-tert-butyl-1-(3-methylphenyl)-1^5-pyrazolyl]-3-{8- {3, 4 - two Hydrogen-5-[2-(4-morphinolinyl)ethoxy] ² -alkenyl}}urea

1- [ (3-叔丁基- 1-萘基） -1^5-吡唑基] -3- {8- {3， 4-二氢 -5- [2- (4-***啉基）乙氧基] -2^·色烯基 } }脲 1-[(3-tert-butyl-1-naphthyl)-1^5-pyrazolyl]-3-{8- {3,4-dihydro-5-[2-(4-morphinolinyl) Ethoxy] -2^·color alkenyl} }urea

1- [3-叔丁基 -1- (4-甲基苯基) -1H-5-吡唑基] -3- {8- {3, 4-二氢- 5- [2- (1-吡唑基）乙氧基] - 色烯基 } }脲 1-[3-tert-Butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{8- {3, 4-dihydro- 5- [2- (1- Pyrazolyl)ethoxy]-chromenyl} }urea

1- [3-叔丁基 - 1- (4-甲基苯基） - 1H-5 吡唑基] -3- {8- {3, 4-二氢 -5- U- (1-哌啶- 4-酮基）乙氧基] -²^~色烯基 } }脲 1-[3-tert-Butyl- 1-(4-methylphenyl)-1H-5pyrazolyl]-3-{8- {3, 4-dihydro-5- U-(1-piperidine - 4-keto)ethoxy] - ² ^~ alkenyl} } Urea

1- [3-叔丁基 -1- (4-甲基笨基) - 1H- 5-吡唑基] -3- {8- {3， 4-二氢 -5- [2- (4-***啉基）乙酰氨基] - 2^·色烯基 } }脲 1-[3-tert-Butyl-1-(4-methylphenyl)-1H- 5-pyrazolyl]-3-{8- {3, 4-dihydro-5- [2- (4- Morpholinyl)acetamido]-2^·enyl}}urea

1- [3-叔丁基 -1- (4-三氟甲基苯基） - 1^"5 -吡唑基] -3- {8- {3， ⁴-二氢- 5- [2- (4-***啉基）乙氧基] - 2^·色烯基 } }脲 1- [3-tert-butyl-1- (4-trifluoromethylphenyl) --1 ^ "5 - pyrazolyl] -3- {8- {3, ⁴ - dihydro --5- [2- (4-morphinolinyl)ethoxy] - 2^·chromenyl} }urea

1- [3-叔丁基 -1- (4-乙基苯基） -1^"5-吡唑基] - 3- {8- {3 , 4-二氢- 5- U- (4-***啉基）乙氧基] - 色烯基脲 1-[3-tert-Butyl-1-(4-ethylphenyl)-1^"5-pyrazolyl]-3-(8-{3,4-dihydro- 5- U- (4- Morpholinyl)ethoxy]-chromenylurea

1 - [3-叔丁基 -1- (4-叔丁基苯基） -1^-5-吡唑基] -3- {8- {3, 4- 二氢 -5- [2- (4-***啉基）乙氧基] -2^·色烯基 } }脲 1-[3-tert-Butyl-1-(4-tert-butylphenyl)-1^-5-pyrazolyl]-3-{8- {3, 4-dihydro-5-[2-( 4-morpholinyl)ethoxy] -2^·chromenyl} }urea

1- [ 3 -叔丁基- 1- (4-三氟甲基苯基) - 1^5-吡唑基] -3- {8- {3 , 4 -二氢 -5- [2- (1-咪唑基）乙氧基] 色烯基 } }脲 1-[ 3 -tert-butyl-1-(4-trifluoromethylphenyl)-1 ^5-pyrazolyl]-3-{8- {3 , 4 -dihydro-5- [2- ( 1-imidazolyl)ethoxy]chromenyl}}urea

1- [3- 叔丁基 -1 -（4- 甲基苯基）-1Η-5- 吡唑基] -3- {8- {5- [2- (4-***啉基）乙氧基] - 色烯基 } }脲 1-[3-tert-Butyl-1 -(4-methylphenyl)-1Η-5-pyrazolyl]-3-{8- {5- [2-(4-morphinolinyl)ethoxy ] - Alkenyl} } Urea

1- [3-叔丁基 -1- (4-甲基苯基） - 1H- 5 -吡唑基] -3- {8- {3， 4 二氢- 5- [2- (4-吡啶基）乙氧基] - 色烯基 } }脲 1-[3-tert-Butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{8- {3, 4 dihydro-5-[2-(4-pyridine Ethyl]-chromenyl} }urea

1- [3-叔丁基 -1- (4-腈基苯基） - 1^5-吡唑基] -3- {8- {3， 4 -二氢 -5- [2- (4-***啉基）乙氧基] -2^·色烯基 H脲 1-[3-tert-Butyl-1-(4-cyanophenyl)-1^5-pyrazolyl]-3-{8- {3, 4-dihydro-5- [2- (4- Morpholine) Ethoxy] -2^·Alkenyl H-urea

1- [3-叔丁基 -1- (3-氯 -4-氟苯基） - 1^~5-吡唑基] -3- {8- {3 , 4 -二氢 -5- [2- (4-***啉基）乙氧基〗色烯基 } }脲 1-[3-tert-Butyl-1-(3-chloro-4-fluorophenyl)-1 ^~5-pyrazolyl]-3-{8- {3 , 4 -dihydro-5- [2 - (4-morphinolinyl)ethoxyl oligolenyl} }urea

[3-叔丁基- 1- (4-甲基苯基) - 1H-5-吡唑基〗 -3- {8- {5- [ (4- 甲氧基苯基）甲氧基] -² 色烯基 } }脲 1- [3-叔丁基 -1- (4-曱基苯基） - 1H-5-吡唑基] -3- {8- [5- (4- ***啉基酰基甲氧基) -2^色烯基] }脲 [3-tert-Butyl- 1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{8- {5-[(4-methoxyphenyl)methoxy]- ^2- color alkenyl} } urea 1-[3-tert-Butyl-1-(4-indolylphenyl)-1H-5-pyrazolyl]-3-{8-[5-(4-morpholinylacylmethoxy)-2 ^色烯]]Urea

1 - [3-叔丁基 -1- (4-氟苯基） - 1^5-吡唑基] -3- {8- {5- [2- (4- ***啉基）乙氧基] - 2 色烯基 }}脲 1-[3-tert-Butyl-1-(4-fluorophenyl)-1^5-pyrazolyl]-3-{8- {5- [2-(4-morphinolinyl)ethoxy] - 2-color alkenyl}}urea

1 - [3-叔丁基 1- (4-氯苯基） - 1^5-吡唑基] -3- {8- {5- [2- (4- ***啉基）乙氧基] - ² 色烯基 }}脲 1-[3-tert-Butyl 1-(4-chlorophenyl)-1^5-pyrazolyl]-3-{8- {5- [2-(4-morphinolinyl)ethoxy]- ^2- color alkenyl}}urea

1- [3-叔丁基 - 1- (4-溴苯基） - l 5-吡唑基] -3- {8- {5- [2- (4- ***啉基）乙氧基] -²^"色烯基脲 1-[3-tert-butyl-1-(4-bromophenyl)-l 5-pyrazolyl]-3-{8- {5-[2-(4-morphinolinyl)ethoxy]- ² ^"Color alkenyl urea

1-（ 3-叔丁基 -1-苯基 -1^5-吡唑基） -3-{8-{5-[2-(4-*** 啉基）乙氧基〗 -²^"色烯基 }}脲 1-( 3-tert-Butyl-1-phenyl-1^5-pyrazolyl)-3-{8-{5-[2-(4-morphinolinyl)ethoxy] - ² ^"色Alkenyl}}urea

1-[3- 叔丁基 - 1-(4- 甲氧基苯基吡唑基]- 3- {8- {5- U - (4-***啉基）乙氧基] - 2 色烯基 }}脲 1-[3-tert-butyl-1-(4-methoxyphenylpyrazolyl)-3-{8-{5- U-(4-morphinolinyl)ethoxy]-2 alkenyl }}urea

1 - [3-叔丁基 - 1- (4-三氟曱基苯基）-1 5- 吡唑基]- 3- {8- {5- [2- (4-***啉基）乙氧基] -2^·色烯基 }}脲 1-[3-tert-butyl-1-(4-trifluorodecylphenyl)-1 5-pyrazolyl]- 3-{8- {5- [2-(4-morphinolinyl)ethoxylate Base] -2^·color alkenyl}}urea

1-[3- 叔丁基 - 1-(4- 硝基苯基）-1^"5- 吡唑基] -3- {8- {5- [2 -（4-***啉基）乙氧基] -2^~色烯基 }}脲 1-[3-tert-butyl-1-(4-nitrophenyl)-1^"5-pyrazolyl]-3-{8- {5-[2-(4-morphinolinyl)ethoxylate Base] -2^~color alkenyl}}urea

1-[3- 叔丁基 -1- (4- 腈基苯基）-1 5- 吡唑基] -3-{8-{5- U-(4-***啉基）乙氧基] 色烯基 }}脲 1-[3-tert-butyl-1-(4-cyanophenyl)-1 5-pyrazolyl]-3-{8-{5- U-(4-morphinolinyl)ethoxy] Alkenyl}}urea

1 - [3- 叔丁基 - 1 -（4- 甲基苯基）-1Η-5- 吡唑基]-3-{8-{5-[2-（1一1, 2, 4-三氮唑基）乙氧基 ]-2 色烯基 }}脲 1-[3-tert-butyl- 1 -(4-methylphenyl)-1Η-5-pyrazolyl]-3-{8-{5-[2-(1,1, 2, 4-three Azazolyl)ethoxy]-2 chromenyl}}urea

1-[3- 叔丁基 - 1-(4- 乙基苯基吡唑基 ]-3-{8- {5-[2- (4-***啉基）乙氧基] - 2 色烯基 }}脲 1-[3-tert-butyl-1-(4-ethylphenylpyrazolyl)-3-{8-{5-[2-(4-morphinolinyl)ethoxy]-2 alkenyl }}urea

1 [3- 叔丁基 -1-(4- 叔丁基苯基 )-1 ~5 - 吡唑基] -3- {8- {5- [2- (4 -***啉基）乙氧基] -29"色烯基 }}脲 1 [3-tert-Butyl-1-(4-tert-butylphenyl)-1 ~5-pyrazolyl]-3-{8- {5- [2-(4- morphinolinyl)ethoxy ] -29"Color Alkenyl}} Urea

1-〖3- 叔丁基 -1-(3- 氯 - 4- 氟苯基）-1 5- 吡唑基]- 3- {S-{⁵- U- (4-***啉基）乙氧基] -²^~色烯基 }}脲 1-[3-tert-Butyl-1-(3-chloro-4-fluorophenyl)-1 5-pyrazolyl]- 3-{S-{ ⁵ - U-(4-morphinolinyl)ethoxylate Base] - ² ^~ alkenyl}}urea

1 - [3-叔丁基 -1-(3 , 4 -二甲基苯基）- 1^~5-吡唑基]-3-{⁸-{⁵-[2-(4-***啉基）乙氧基] - 2 色烯基 }}脲 1-[3-tert-butyl-1-(3 , 4 -dimethylphenyl)-1 ^~5-pyrazole ]]-3-{ ⁸ -{ ⁵ -[2-(4-morphinolinyl)ethoxy] - 2 alkenyl}}urea

1 - [3- 叔丁基 - 1-(3 ， 4- 二氯苯基 )-1 ~5- 吡唑基]-³-{⁸-{⁵-[2-（4-***啉基）乙氧基] -2 色烯基 }}脲 1-[3-tert-butyl-l-(3,4-dichlorophenyl)-1~5-pyrazolyl]- ³ -{ ⁸ -{ ⁵ -[2-(4-morphinolinyl) Oxy] -2 color alkenyl}}urea

1- (3-叔丁基 -5-异喁唑基） -3- {8- {5- [2- (4-***啉基）乙氧基〗 -2 色烯基 }}脲 1-(3-tert-butyl-5-isoxazolyl)-3-{8-{5-[2-(4-morphinolinyl)ethoxy]-2-alkenyl }}urea

1-（5-叔丁基 -3-异喁唑基） -3- {8- {5- [2- (4-***啉基）乙氧基] - ² 色烯基 }}脲 1-(5-tert-Butyl-3-isoxazolyl)-3-{8-{5-[2-(4-morphinolinyl)ethoxy] ^{-2 2} -alkenyl}}urea

1-[1- 叔丁基 -3-（4- 甲基苯基）-1^-4- 吡唑基] -3- {8- {⁵- [2- (4-***啉基）乙氧基] - ² 色烯基 }}脲 1-[1-tert-butyl-3-(4-methylphenyl)-1^-4-pyrazolyl]-3-{8- { ⁵ - [2- (4-morphinolinyl) ethoxylate Base] - ^2- color alkenyl}}urea

1-[3- 叔丁基 - 1- (3- 甲基苯基 )-lff~5- 吡唑基] -3 - {8- {5- [2- (4-***啉基）乙氧基〗 -2^-色烯基 }}脲 1-[3-tert-butyl-1-(3-methylphenyl)-lff~5-pyrazolyl]-3-{8-{5-[5-[2-(4-morphinolinyl)ethoxylate 〖 -2^-color alkenyl}}urea

1- [ (3-叔丁基 -1-萘基） - 1^~5-吡唑基] -3- {8- {5- [2- (4-*** 啉基）乙氧基] - 2 色烯基 }}脲 1-[(3-tert-Butyl-1-naphthyl)-1^~5-pyrazolyl]-3-{8- {5- [2-(4-morphinolinyl)ethoxy]-2 Alkenyl}}urea

1-[4- 叔丁基 - 1-（4- 甲基苯基）- 1^2- 咪唑基] -3- {8- {5- [2- (4-***啉基）乙氧基] - 2 色烯基 }}脲 1-[4-tert-butyl-1-(4-methylphenyl)- 1^2-imidazolyl]-3-{8- {5-[2-(4-morphinolinyl)ethoxy] - 2-color alkenyl}}urea

1 - [3- 叔丁基 -1-(4- 甲基苯基）-1Η- 5- 吡唑基]- 3- {8- {5- {2- [4- (顺式 -2, 6-二甲基）***啉基]乙氧基 } -2H- 色烯基脲 1-[3-tert-Butyl-1-(4-methylphenyl)-1Η- 5-pyrazolyl]- 3- {8- {5- {2- [4- (cis-2, 6 -dimethyl)morphinolinyl]ethoxy}-2H-chromenylurea

以及其可药用盐或溶剂化物。式 I的化合物的制备： And pharmaceutically acceptable salts or solvates thereof. Preparation of compounds of formula I:

式 I的化合物可以由下面的几种方法制备，优选方法 3。方法 1

The compound of formula I can be prepared by several methods, preferably method 3. method 1

R. = OPh, CCL R. = OPh, CCL

方法 3 Method 3

R₆0 OR₆ ~~ - _A 人。 _Re

R ₆ 0 OR ₆ ~~ - _A person. _Re

R₆ = CCI₃, C₆H₄N0₂, OC₂H₅, imidiazole, Triazole R ₆ = CCI ₃ , C ₆ H ₄ N0 ₂ , OC ₂ H ₅ , imidiazole, Triazole

上述三种方法的反应次序可以颠倒，即光气，氯甲酸酯或碳酸酯可以先与 P-L-Ar₂-NH₂反应，生成的中间体再与 A_riNH₂反应。 The reaction sequence of the above three methods can be reversed, that is, phosgene, chloroformate or carbonate can be first reacted with PL-Ar ₂ -NH ₂ , and the resulting intermediate is further reacted with A _ri NH ₂ .

Ar_{1 ?} Ar₂， L, P的定义同通式 I。 Ar _{1 ?} Ar ₂ , L, P are as defined for Formula I.

在方法 1中，一种杂环胺溶于二氯甲烷，氯仿或二氯乙垸中，加入碳酸氢钠或者碳酸钟的水溶液，水水浴中冷却，加入光气，搅拌 5-30分钟，得到的中间体与另一杂环胺在无水的非质子性溶剂中（如 THF， ***，甲苯，二氧六环，二氯甲烷，乙酸乙酯等）于 0-45°C反应 2-24小时得到式 I的化合物。 In the method 1, a heterocyclic amine is dissolved in dichloromethane, chloroform or dichloroacetic acid, added with an aqueous solution of sodium hydrogencarbonate or carbonic acid, cooled in a water bath, added with phosgene, stirred for 5-30 minutes, The intermediate is reacted with another heterocyclic amine in an anhydrous aprotic solvent (eg THF, diethyl ether, toluene, dioxane, dichloromethane, ethyl acetate, etc.) at 0-45 ° C. 2-24 The compound of formula I is obtained in an hour.

在方法 2中，一种杂环胺溶于二氯曱烷，氯仿或二氯乙烷中，加入适当的碱（如三乙胺等），然后加入氯甲酸酯，于 0-85 Ό反应 2 - 24小时，得到的中间体与另一杂环胺在无水的非廣子性溶剂中（如 THF, ***，甲苯，二氧六环，二氯甲烷，乙酸乙酯等）于 0- 110°C反应 2-24小时得到式 I的化合物。在方法 3中，一种杂环胺溶于二氯甲烷，氯仿或二氯乙烷中，加入适当的碱（如三乙胺等），然后加入碳酸酯，于- 20-45Ό反应 2-24小时，得到的中间体与另一杂环胺在无水的非质子性溶剂中（如 THF, ***，甲苯，二氧六环，二氯甲烷，乙酸乙酯等）于 0- 110Ό反应 2-240小时得到式 I的化合物。 In Method 2, a heterocyclic amine is dissolved in dichloromethane, chloroform or dichloroethane, added with a suitable base (such as triethylamine, etc.), then added with a chloroformate, and reacted at 0-85 Torr. 2 - 24 hours, the obtained intermediate and another heterocyclic amine in an anhydrous non-porous solvent (such as THF, diethyl ether, toluene, dioxane, dichloromethane, ethyl acetate, etc.) at 0-110 The reaction at ° C for 2 to 24 hours gives the compound of formula I. In Process 3, a heterocyclic amine is dissolved in dichloromethane, chloroform or dichloroethane, added with a suitable base (such as triethylamine, etc.), then carbonate is added, and the reaction is carried out at - 20-45 Torr. In an hour, the obtained intermediate is reacted with another heterocyclic amine in an anhydrous aprotic solvent (such as THF, diethyl ether, toluene, dioxane, dichloromethane, ethyl acetate, etc.) at 0-110 Torr. The compound of formula I is obtained in 240 hours.

Ar^I^根据结构的不同，分别由以下路线合成。 Rl， R2 定义同通式 I。 Ar^I^ is synthesized by the following routes according to the structure. Rl, R2 are defined as the same formula I.

( 1 ) 3-氨基吡唑类 (1) 3-aminopyrazoles

1. NaN02 1. NaN02

R₂-NH₂ R₂-NHNH₂ R ₂ -NH ₂ R ₂ -NHNH ₂

2.还原 2. Restore

II II

胺于 -10— 10。C经过重氩化反应得到重氮盐，重氮盐经亚硫酸钠或氯化亚锡还原得到肼 Π。取代的氯甲基酯在无水四氢呋喃中，在氢化钠等碱的作用下与无水乙腈回流反应得到中间体 m;

The amine is at -10-10. C is subjected to heavy argonization to obtain a diazonium salt, and the diazonium salt is reduced by sodium sulfite or stannous chloride to obtain hydrazine. The substituted chloromethyl ester in anhydrous tetrahydrofuran, under the action of a base such as sodium hydride and reflux with anhydrous acetonitrile to obtain an intermediate m;

ΙΠ和 Π在酸性条件下，在乙醇中回流 16 48小时，得到 3-氨基吡唑 IV。 The hydrazine and hydrazine were refluxed in ethanol under acidic conditions for 16 48 hours to give 3-aminopyrazole IV.

( 2 ) 3-氨基呋喃类 ( 2 ) 3-aminofuran

酰基乙酸乙酯在强碱（钠，氢化钠，乙醇钠等）的作用下与 α -溴代酮反应，得到的二酮酯 V在乙醇等溶剂中和硫酸或盐酸反应得到 3-呋喃甲酸乙酯 VI， 3-呋喃甲酸乙酯 VI和水合肼以及甲酸反应得到 3-氨基呋喃类化合物 VII。 Ethyl acetate is reacted with α-bromo ketone under the action of a strong base (sodium, sodium hydride, sodium ethoxide, etc.), and the obtained diketoester V is reacted with sulfuric acid or hydrochloric acid in a solvent such as ethanol to obtain 3-furancarboxylic acid B. Ester VI, ethyl 3-furancarboxylate VI and hydrazine hydrate and formic acid are reacted to give 3-aminofuran compound VII.

( 3 ) 3-氨基噻吩类 (3) 3-aminothiophenes

二酮和 Lawesson' s试剂在无水的非质子性溶剂中回流反应 1-10 小时得到取代的噻吩，然后经浓硝酸硝化，铁 /盐酸或催化氢化还原得到 3-氨基噻吩类化合物 VIII。

The diketone and Lawesson's reagent are refluxed in an anhydrous aprotic solvent for 1-10 hours to obtain a substituted thiophene, which is then nitrated by concentrated nitric acid, iron/hydrochloric acid or catalytic hydrogenation to give 3-aminothiophene compound VIII.

( 4 ) 2-氨基吡咯类、 N(4) 2-Aminopyrroles , N

K X K X

腈基醛和取代的胺在乙酸 /水中于 50-90。C反应 ⁵_30分钟得到氨基腈 IX， IX在乙醇钠的存在下于室温环合生成 ²-氨基吡咯类化合物 X。 The nitrile aldehyde and the substituted amine are in the range of 50-90 in acetic acid/water. C reaction ⁵ -30 minutes to obtain aminonitrile IX, IX is cyclized at room temperature in the presence of sodium ethoxide to form ² -aminopyrrole X.

( 5 ) 4-氨基喁唑类

(5) 4-aminocarbazole

XI XI

酰基腈，醛，无水乙酸铵在乙酸中回流 3-6小时，得到 4-氨基§ 唑类化合物 XI。 The acyl nitrile, aldehyde, and anhydrous ammonium acetate are refluxed in acetic acid for 3-6 hours to give 4-amino § azole compound XI.

( 6 ) 5-氨基喁唑类

(6) 5-aminocarbazole

ΧΠ ΧΠ

XIII XIV XIII XIV

酰氯与腈基胺在 0°C，在四氢呋喃等溶剂中反应得到酰胺 Π: ΧΠ溶解在干燥的二氯甲烷中，加入乙硫醇，通入干燥氯化氢气体, 反应 5-30分钟，得到的产品 xm于 o ,在干燥的吡啶中通入硫化氢至饱和， 4小时后得到 5-氨基喁唑类化合物 XIV。 The acid chloride is reacted with a nitrileamine at 0 ° C in a solvent such as tetrahydrofuran to obtain an amide oxime: hydrazine is dissolved in dry dichloromethane, ethanethiol is added, and dry hydrogen chloride gas is introduced. The reaction is carried out for 5-30 minutes, and the obtained product xm is at o. Hydrogen sulfide is introduced into the dried pyridine to saturation, and after 5 hours, the 5-aminocarbazole compound XIV is obtained.

(7) 5-氨基噻唑类 (7) 5-aminothiazoles

氨基腈，硫磺溶于干燥的甲醇或乙醇，滴加三乙胺，加热到 50°C，反应 1-3小时，得到产物 XV, XV经盐酸或对甲苯磺酸水解得到 5-氨基噻唑 XVI。 Aminonitrile, sulfur is dissolved in dry methanol or ethanol, triethylamine is added dropwise, and heated to 50 ° C for 1-3 hours to obtain product XV. XV is hydrolyzed with hydrochloric acid or p-toluenesulfonic acid to give 5-aminothiazole XVI.

(8) 2-氨基咪唑类

(8) 2-aminoimidazoles

νπ Νπ

在碱（碳酸氢钟，碳酸钟等）存在下， α-氯代酮与取代的胺在 DMF等溶剂中反应得到 α -氨基酮 X Vn， X VII在乙醇等溶剂中和腈胺回流 12小时得到 2-氨基咪唑 X覆。 In the presence of a base (carbonic acid clock, carbonic acid clock, etc.), the α-chloroketone is reacted with a substituted amine in a solvent such as DMF to obtain an α-aminoketone X Vn, and X VII is refluxed with a nitrileamine in a solvent such as ethanol for 12 hours. 2-Aminoimidazole X was obtained.

( 9 ) 4-氨基吡唑类 (9) 4-aminopyrazoles

χκ Χκ

χχ XXI 入入 ¹¹ 氯代酮与邻苯二曱酰亚胺钾盐在 DMF中于反应 2小时，得到化合物 ΧΚ, XIX与 Ν，Ν-二甲基甲酰胺二甲基缩醛在 DMF中于 100°C反应 12小时，得到化合物 XX。 XX和取代的肼在 90% 乙醇中回流 I²小时得到化合物 XX I , XX I在乙醇中肼解得到 4 -氨基吡唑 XX Π。

Χχ XXI is added to ¹¹ chloroketone and phthalic acid imide potassium salt in DMF for 2 hours to obtain the compound ΧΚ, XIX and Ν, Ν-dimethylformamide dimethyl acetal in DMF The reaction was carried out at 100 ° C for 12 hours to give the compound XX. XX and substituted hydrazine are refluxed in 90% ethanol for ¹² hours to give compound XX I, XX I is decomposed in ethanol to give 4-aminopyrazole XX oxime.

(10) 5-氨基异噁唑类

(10) 5-aminoisoxazoles

XXIII XXIII

腈基酮再碱性条件下于 50-ΙΟΟ 与盐酸羟胺反应，得到 5- 氨基异喁唑 XX m。 The cyanoketone is reacted with 50% hydrazine under basic conditions with hydroxylamine hydrochloride to give 5-aminoisoxazole XX m.

本领域技术人员应该意识到，本发明化合物也可以以其可药用盐或溶剂化物的形式使用。通式 I化合物的生理学上可接受的盐包括由药学上可接受的无机酸或有机酸或者无机碱或有机碱形成的常规的盐以及季铵的酸加成盐。合适的酸盐的更具体的例子包括盐酸、氢溴酸、硫酸、磷酸、硝酸、高氯酸、富马酸、乙酸、丙酸、琥珀酸、羟基乙酸、甲酸、乳酸、马来酸、酒石酸、柠檬酸、朴酸、丙二酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、富马酸、甲苯磺酸、甲磺酸、萘 -2-磺酸、苯磺酸、羟基萘甲酸、氢碘酸、苹果酸、 s teroic、鞣酸等的盐。其它的酸，如草酸，虽然其本身并非药学上可接受的，但可以用于制备用作中间体的盐，以获得本发明化合物及其可药用盐。合适的碱盐的更具体的例子包括钠、裡、钾、镁、铝、钙、锌、 N，N， -二苄基乙二胺、氯代普鲁卡因、胆碱、二乙醇胺、乙二胺、 N-甲基葡糖胺和普鲁卡因盐。此后涉及到本发明的化合物时，包括通式 I化合物及其可药用盐和溶剂化物。 Those skilled in the art will appreciate that the compounds of the invention may also be used in the form of their pharmaceutically acceptable salts or solvates. Physiologically acceptable salts of the compounds of formula I include conventional salts formed from pharmaceutically acceptable inorganic or organic acids or inorganic or organic bases, and quaternary ammonium acid addition salts. More specific examples of suitable acid salts include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetic acid, propionic acid, succinic acid, glycolic acid, formic acid, lactic acid, maleic acid, tartaric acid. , citric acid, citric acid, malonic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, water Salts of salicylic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, hydroxynaphthoic acid, hydroiodic acid, malic acid, s teroic, citric acid and the like. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, can be used in the preparation of salts useful as intermediates to obtain the compounds of the invention and their pharmaceutically acceptable salts. More specific examples of suitable base salts include sodium, hydrate, potassium, magnesium, aluminum, calcium, zinc, N,N,-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, B. Diamine, N-methylglucamine and procaine salts. Hereinafter, when referring to the compounds of the present invention, the compounds of formula I, and pharmaceutically acceptable salts and solvates thereof, are included.

本发明还包括本发明化合物的前药，该前药一经给药，即通过代谢过程进行化学转化，之后变成具有活性的药物。通常，这类前药是本发明化合物的功能性衍生物，其在体内容易转化成所需的式（I)的化合物。例如，在 "Design Of Prodrugs" ， H Bund Saard, Elsevier编辑， 1985中描述了选择和制备适宜前药衍生物的常规方法。 The present invention also encompasses prodrugs of the compounds of the invention which, upon administration, are chemically converted by metabolic processes and thereafter become active drugs. Typically, such prodrugs are functional derivatives of the compounds of the invention which are readily converted in vivo to the desired compound of formula (I). For example, conventional methods for selecting and preparing suitable prodrug derivatives are described in "Design Of Prodrugs", H Bund Saard, Elsevier, ed., 1985.

本发明也包括本发明化合物的活性代谢物。 The invention also includes active metabolites of the compounds of the invention.

本发明的另一个方面涉及药物组合物，其含有本发明化合物和至少一种药学上可接受的载体，其可用于体内治疗并具有生物相容性。所述药物组合物可以根据不同给药途径而制备成各种形式。本发明所提及的化合物也可以被制备成各种药学可接受的盐。 Another aspect of the invention relates to a pharmaceutical composition comprising a compound of the invention and at least one pharmaceutically acceptable carrier which is useful for in vivo treatment and is biocompatible. The pharmaceutical compositions can be prepared in a variety of forms depending on the route of administration. The compounds referred to in the present invention can also be prepared into various pharmaceutically acceptable salts.

本发明的化合物对 PPAR 的激动作用可以用下述方法进行测定。将 THP- 1细胞悬浮于含有 15%胎牛血清， 0. 02 nM 2-巯基乙醇的 RMPI培养基中，细胞浓度为 1-2 10⁶个细胞 /mL，然后在 96 孔平板上铺板（每孔含 0. 2 mL ) 。实验化合物在 DMS0中溶解，然后用培养基稀释，使 DMS0的终浓度为 5%。向每孔加入 25 实验化合物溶液或仅有 DMS0的培养基（对照）。 ' 将细胞与实验化合物的系列稀释液一起于 37 Ό保温 30分钟，然后加入 IFN- γ (

) ,并继续保温 18-24 N2008/000760 小时，于 1600RPM离心 10分钟终止保温。用市售的 ELISA试剂盒分析上清液中的 TNF- α含量。将本发明的化合物以 0. 1-3 μ Μ的浓度进行实验。代表性的本发明的化合物可以在实验中抑制 TNF - α释放。 The agonistic effect of the compound of the present invention on PPAR can be measured by the following method. The THP- 1 cells were suspended in fetal calf serum containing 15%, 0. 02 nM 2- RMPI medium-mercaptoethanol at a cell concentration of 1-2 ¹⁰⁶ cells / mL, and plated in 96 well plates (each The pores contain 0.2 mL). The test compound was dissolved in DMS0 and then diluted with a medium to give a final concentration of DMSO of 5%. 25 test compound solutions or DMSO only medium (control) were added to each well. ' Incubate the cells with serial dilutions of the test compound for 30 minutes at 37 °C, then add IFN-γ (

) and continue to keep warm 18-24 N2008/000760 hours, the incubation was terminated by centrifugation at 1600 RPM for 10 minutes. The TNF-α content in the supernatant was analyzed using a commercially available ELISA kit. The compound of the present invention was tested at a concentration of 0.1 to 3 μM. Representative compounds of the invention may inhibit TNF-[alpha] release in the assay.

表 1部分本发明化合物对 TNF- α的抑制作用（ 3 μ Μ ) Table 1 Inhibition of TNF-α by the compounds of the invention (3 μ Μ )

本发明化合物的药物組合物可以以下面的任意方式施用：口服，喷雾吸入，直肠用药，鼻腔用药，颊部用药，局部用药，非肠道用药，如皮下、静脉、肌内、腹膜内、鞘内、心室内、胸骨内和颅内注射或输入，或借助一种外植储器用药。其中优选口服、腹膜内或静脉内给药方式。

The pharmaceutical composition of the compound of the present invention can be administered in any of the following ways: oral, spray inhalation, rectal administration, nasal administration, buccal administration, topical administration, parenteral administration, such as subcutaneous, intravenous, intramuscular, intraperitoneal, sheath Intra, intraventricular, intrasternal, and intracranial injection or input, or by means of an explant reservoir. Among them, oral, intraperitoneal or intravenous administration is preferred.

当口服用药时，本发明化合物可制成任意口服可接受的制剂形式，包括但不限于片剂、胶袭、水溶液或水悬浮液。其中，片剂使用的载体一般包括乳糖和玉米淀粉，另外也可加入润滑剂如硬脂酸镁。胶袁制剂使用的稀释剂一般包括乳糖和干燥玉米淀粉。水悬浮液制剂则通常是将活性成分与适宜的乳化剂和悬浮剂混合使用。如果需要，以上口服制剂形式中还可加入一些甜味剂、芳香剂或着色剂。 When administered orally, the compounds of the invention may be formulated in any orally acceptable form including, but not limited to, tablets, gels, aqueous solutions or aqueous suspensions. Among them, the carrier used for the tablet generally includes lactose and corn starch, and a lubricant such as magnesium stearate may also be added. The diluent used in the gelatin preparation generally comprises lactose and dried corn starch. Aqueous suspension preparations are usually prepared by mixing the active ingredient with suitable emulsifying and suspending agents Use. If desired, some of the above oral preparation forms may also contain some sweeteners, fragrances or colorants.

当局部用药时，特别是治疗局部外敷容易达到的患面或器官，如眼睛、皮肤或下肠道神经性疾病时，可才艮据不同的患面或器官将本发明化合物制成不同的局部用药制剂形式，具体说明如下：当眼部局部施用时，本发明化合物可配制成一种微粉化悬浮液或溶液的制剂形式，所使用载体为等渗的一定 pH的无菌盐水，其中可加入也可不加防腐剂如氯化苄基烷醇盐。对于眼用，也可将化合物制成骨剂形式如凡士林骨。 When applied topically, especially in the treatment of facial or organs easily accessible by topical application, such as eye, skin or lower intestinal neuropathy, the compounds of the invention may be made into different parts according to different affected faces or organs. The form of the pharmaceutical preparation is specifically described as follows: When the eye is topically applied, the compound of the present invention can be formulated into a preparation form of a micronized suspension or solution, and the carrier used is an isotonic pH-stabilized saline solution, which can be added thereto. There may be no preservatives such as benzyl chloride alkoxide. For ophthalmic use, the compound can also be formulated into a bone form such as vaseline.

当皮肤局部施用时，本发明化合物可制成适当的软骨、洗剂或霜剂制剂形式，其中将活性成分悬浮或溶解于一种或多种载体中。软骨制剂可使用的载体包括但不限于：矿物油，液体凡士林，白凡士林，丙二醇，聚氧化乙烯，聚氧化丙烯，乳化蜡和水；洗剂或霜剂可使用的载体包括但不限于：矿物油，脱水山梨糖醇单硬脂酸酯，吐温 60, 十六烷酯蜡，十六碳烯芳醇， 2-辛基十二垸醇，苄醇和水。 When applied topically to the skin, the compounds of the invention may be formulated in a suitable cartilage, lotion or cream formulation wherein the active ingredient is suspended or dissolved in one or more carriers. Carriers for cartilage preparations include, but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; lotions or creams may be used including but not limited to: minerals Oil, sorbitan monostearate, Tween 60, cetyl esters wax, hexadecene aryl alcohol, 2-octyldodecanol, benzyl alcohol and water.

本发明化合物还可以无菌注射制剂形式用药，包括无菌注射水或油悬浮液或无菌注射溶液。其中，可使用的载体和溶剂包括水、林格氏溶液和等渗氯化钠溶液。另外，灭菌的非挥发油也可用作溶剂或悬浮介质，如单甘油酯或二甘油酯。 The compounds of the present invention can also be administered in the form of a sterile injectable preparation, including sterile aqueous or oily suspension or sterile injection solutions. Among them, carriers and solvents which can be used include water, Ringer's solution and isotonic sodium chloride solution. Alternatively, sterilized, fixed oils may be employed as a solvent or suspension medium such as a monoglyceride or a diglyceride.

另外需要指出，本发明化合物的使用剂量和使用方法取决于诸多因素，包括患者的年龄、体重、性别、自然健康状况、营养状况、化合物的活性强度、服用时间、代谢速率、病症的严重程度以及诊治医师的主观判断。优选的使用剂量介于 0. 01 ~ 100mg/kg体重 /天，其中最优剂量在 5mg/kg 10mg/kg体重 /天。具体实施方式本发明用下述的中间体和实施例进一步说明，这些中间体和实施例不构成对本发明的限制。 It should also be noted that the dosage and method of use of the compounds of the invention depends on a number of factors, including the age, weight, sex, natural health, nutritional status of the compound, the strength of the compound, the time of administration, the rate of metabolism, the severity of the condition, and Subjective judgment of the doctor. A preferred dosage is from 0.01 to 100 mg/kg body weight per day, wherein the optimal dose is 5 mg/kg 10 mg/kg body weight per day. detailed description The invention is further illustrated by the following intermediates and examples which are not intended to limit the invention.

化合物熔点由 YRT-3型熔点仪测定，温度未经校正。 NMR 光谱由 Bruker ARX 400型核磁仪测定。 FAB质谱由 Zabspect 高分辨磁质谱仪测定。中间体的制备 The melting point of the compound was determined by a YRT-3 type melting point apparatus, and the temperature was not corrected. NMR spectra were determined by a Bruker ARX 400 nuclear magnetic instrument. FAB mass spectra were determined by a Zabspect high resolution magnetic mass spectrometer. Preparation of intermediates

由芳香胺制备 2 , 5-二取代的 3-氨基吡唑的一般操作 A General procedure for the preparation of 2,5-disubstituted 3-aminopyrazoles from aromatic amines A

1. NaN02 / HCI 1. NaN02 / HCI

R2— NH 2 R2— NHNH, R2—NH 2 R2—NHNH,

2. SnCI2 I HCI 2. SnCI2 I HCI

1. 芳香胺（ 0. 04 fflol )加入 40mL浓盐酸中，搅拌，冷却到 - 5 °C，析出白色细小颗粒状晶体。慢慢滴加亚硝酸钠溶液（2. 90g 亚硝酸钠溶于 20mL水），控制温度不超过 0°C , 加完后反应 1小时。 1. Aromatic amine (0.04 fflol) was added to 40 mL of concentrated hydrochloric acid, stirred, and cooled to -5 °C to precipitate white fine granular crystals. Slowly add sodium nitrite solution (2. 90g sodium nitrite dissolved in 20mL water), control the temperature does not exceed 0 °C, and react for 1 hour after the addition.

2. 18. Og氯化亚锡溶于 50mL浓盐酸，冷却到 -5 °C , 滴加步骤 1制备的重氮盐溶液，析出白色晶体，反应 1小时，过滤，滤饼干燥即得产品芳香肼盐酸盐。 2. 18. Og stannous chloride is dissolved in 50mL concentrated hydrochloric acid, cooled to -5 °C, the diazonium salt solution prepared in step 1 is added dropwise, white crystals are precipitated, reacted for 1 hour, filtered, and the filter cake is dried to obtain aroma of the product. Hydrazine hydrochloride.

3. 30mL无水 THF在加入氢化钠（ 0. 6g， 60%， 0. 015mol ), 搅拌下加入取代的羧酸氯甲酯（ 0. Olmol )和无水乙腈（ 0. 82g, 0. 02mol ) , 加完后先室温反应 1小时，然后加热回流 24小时。冷却，倒入 l OOmL冰水中，用稀盐酸调到 pH 4 , 乙酸乙酯提取，干燥，浓缩，得到粗品。不纯化，直接用于下一步的反应。 The addition of sodium hydride (0.6 g, 60%, 0. 015 mol) was added to the substituted chloromethyl ester of the carboxylic acid (0. Olmol) and anhydrous acetonitrile (0. 82 g, 0.02 mol). After the addition, the reaction was carried out at room temperature for 1 hour, and then heated to reflux for 24 hours. Cool, pour into 100 mL of ice water, adjust to pH 4 with dilute hydrochloric acid, and extract with ethyl acetate. Dry and concentrate to give a crude product. Not purified, used directly in the next reaction.

4. 步骤 3得到的酰基乙腈（1. 25g， 0. Olmol )和步骤 2得到的芳香肼盐酸盐加入到 50mL乙醇中，滴加 2. OmL浓盐酸，加热回流 12- 24小时。冷却，倒入 lOOmL水水中，用稀氢氧化钠调到 PH 12 , 乙酸乙酯提取，干燥，将得到的粗产物经硅胶柱层析，得到白色固体产品。 4. The acyl acetonitrile (1.25 g, 0. Olmol) obtained in the step 3 and the aromatic hydrazine hydrochloride obtained in the step 2 are added to 50 mL of ethanol, and 2. OmL of concentrated hydrochloric acid is added dropwise, and the mixture is heated to reflux for 12-24 hours. The mixture was cooled, poured into 100 mL of water, adjusted to pH 12 with dilute sodium hydroxide, extracted with ethyl acetate and dried. The obtained crude product was subjected to silica gel column chromatography to afford white solid product.

中间体 1

Intermediate 1

标题化合物以对特丁基氯甲酯为原料如一般操作 A, The title compound is prepared by using p-butyl chloromethyl ester as a general material,

所述制备，得浅黄色油状物。 The preparation gave a pale yellow oil.

中间体 2

Intermediate 2

标题化合物以 3 , 4-二甲基苯胺为原料如一般操作 A,步驟 1， 2所述制备，得白色固体。 The title compound was obtained as a white solid using 3,4-dimethylaniline as a material.

中间体 3 Intermediate 3

标题化合物以 3， 4-二氯苯胺为原料如一般操作 A，步骤 1 , 2所述制备，得白色固体。 The title compound was obtained as a white solid using 3,4-dichloroaniline as a starting material as in General procedure A, Steps 1 and 2.

中间体 4

标题化合物以 3-甲基苯胺为原料如一般操作 A, 步骤 1 , 2 所述制备，得白色固体。 Intermediate 4

The title compound was obtained as a white solid using 3-methylaniline as a starting material, as in General Procedure A, Steps 1 and 2.

中间体 5

Intermediate 5

标题化合物以 1-萘胺为原料如一般操作 A, 步骤 1， 2所述制备，得白色固体。 The title compound was prepared as a white solid using 1-naphthylamine as a starting material as in General procedure A, Steps 1 and 2.

中间体 6 Intermediate 6

标题化合物以 3-氯 4-氟苯胺为原料如一般操作 A，步骤 1 , 2 所述制备，得白色固体。 The title compound was obtained as a white solid, using 3-chloro 4-fluoroaniline as a starting material as in General procedure A, Steps 1 and 2.

中间体 7 Intermediate 7

标题化合物以 4 -乙基苯胺为原料如一般操作 A, 步驟 1， 2 所迷制备，得白色固体。 The title compound was obtained as a white solid using 4-ethylaniline as a crude material.

中间体 8 Intermediate 8

标题化合物以 4-异丙基苯胺为原料如一般操作 A，步驟 1， 2 所述制备，得白色固体。中间体 9 The title compound was obtained as a white solid from 4-isopropyl aniline as a general procedure A, Steps 1 and 2. Intermediate 9

标题化合物以 4-三氟甲基苯胺为原料如一般操作 A, 步骤 1， 2所述制备，得白色固体。 The title compound was obtained as a white solid.

中间体 10 Intermediate 10

标题化合物以 4-腈基苯胺为原料如一般操作 A，步驟 1， 2 所迷制备，得白色固体。 The title compound was obtained as a white solid.

中间体 11 Intermediate 11

标题化合物以中间体 1和对甲基苯肼为原料如一般操作 A，步骤 4所述制备，得白色固体。 The title compound was prepared using Intermediate 1 and p-methylphenyl hydrazide as a crude material.

-醒 ( CDC1₃， 400 MHz ) 5 : 7. 40 (d, 2H， /=8. 4 Hz) , 7. 25 (d, 2H, /=3, 08 Hz) , 5. 50 (s, 1H)， 3. 72 (s, 2H)， 2. 37 (s, 3H) , 1. 32 (s, 9H)。 - wake up (CDC1 ₃ , 400 MHz ) 5 : 7. 40 (d, 2H, /=8. 4 Hz) , 7. 25 (d, 2H, /=3, 08 Hz) , 5. 50 (s, 1H ), 3. 72 (s, 2H), 2. 37 (s, 3H), 1. 32 (s, 9H).

中间体 12

Intermediate 12

标题化合物以中间体 1和苯肼为原料如一般操作 A, 步骤 4 所述制备，得白色固体。 The title compound was prepared using Intermediate 1 and phenylhydrazine as a crude material.

中间体 13 Intermediate 13

标题化合物以中间体 1和对甲氧基苯肼为原料如一般操作 A, 步骤 4所述制备，得白色固体。 The title compound was prepared from Intermediate 1 and p-methoxyphenyl hydrazide as described in General Procedure A, Step 4 to give a white solid.

中间体 14 Intermediate 14

标题化合物以中间体 1和 The title compound is intermediate 1 and

骤 4所述制备，得白色固体。 Prepared as described in step 4 to give a white solid.

中间体 15

Intermediate 15

标题化合物以中间体 1和对氯苯肼为原料如一般操作 A, 步骤 4所迷制备，得白色固体。 The title compound was prepared from Intermediate 1 and p-chlorophenyl hydrazide as a general procedure A, Step 4 to give a white solid.

中间体 16 Intermediate 16

标题化合物以中间体 1和对溴苯肼为原料如 The title compound is based on intermediate 1 and p-bromophenyl hydrazine.

中间体 17 Intermediate 17

标题化合物以中间体 1和对硝基苯肼为原料如一般操作 A, 步骤 4所述制备，得黄色固体。 The title compound was prepared from Intermediate 1 and p-nitrophenyl hydrazide as described in General Procedure A, Step 4 to give a yellow solid.

中间体 18 Intermediate 18

标题化合物以中间体 1和对氨基磺酰基苯肼为原料如一般操作 A，步骤 4所述制备，得白色固体。 The title compound was prepared as a starting material from Intermediate 1 and p-aminosulfonylphenyl hydrazide as in General procedure A, step 4 to afford a white solid.

中间体 19 Intermediate 19

标题化合物以中间体 1和中间体 2为原料如一般操作 A, 步骤 4所述制备，得白色固体。 The title compound was prepared from Intermediate 1 and Intermediate 2 as a crude m.

^-NMR (CDC1₃, 400MHz ) δ: 7.18-7.30 (m, 3H) , 5.49(s, 1H), 3.70(s， 2H)， 2.28 (s, 3H) , 2.27(s, 3H) , 1.32 (s, 9H) ₀ 中间体 20 ^-NMR (CDC1 ₃ , 400MHz ) δ: 7.18-7.30 (m, 3H), 5.49(s, 1H), 3.70(s, 2H), 2.28 (s, 3H), 2.27(s, 3H), 1.32 ( s, 9H) ₀ intermediate 20

标题化合物以中间体 1和中间体 3为原料如一般操作 A, 步骤 4所述制备，得白色固体。 The title compound was prepared as a starting material from Intermediate 1 and Intermediate 3.

'H-NMR (CDCI3, 400MHz ) δ: 7.76 (t, 1H)， 7.49 (m, 2H)， 5.53 (s, 1H)， 3.72 (s, 2H) , 1.30 (s 'H-NMR (CDCI3, 400MHz) δ: 7.76 (t, 1H), 7.49 (m, 2H), 5.53 (s, 1H), 3.72 (s, 2H), 1.30 (s

中间体 21 Intermediate 21

标题化合物以中间体 1和中间体 4为原料如一般操作 A, 步骤 4所述制备，得白色固体。 The title compound was prepared from Intermediate 1 and Intermediate 4 using mp.

^-NMR (CDC1₃, 400MHz ) δ: 7.38 (s, 1H)， 7.31-7.33 (m, 2H), 7.13(m, 1H) , 5.51 (s, 1H)， 3.73(s, 2H) , 2.39 (s, 3H)， 1.31 (s, 9H)。 ^-NMR (CDC1 ₃ , 400MHz ) δ: 7.38 (s, 1H), 7.31-7.33 (m, 2H), 7.13 (m, 1H), 5.51 (s, 1H), 3.73 (s, 2H), 2.39 ( s, 3H), 1.31 (s, 9H).

中间体 22 Intermediate 22

标题化合物以中间体 1和中间体 5为原料如一般操作 A, 步骤 4所述制备，得白色固体。 The title compound was prepared from Intermediate 1 and Intermediate 5 using mp.

'H-NMRCCDCls, 400MHz ) δ: 7.89-7.91 (m, 2H)， 7.51-7.55 (m， 5H)， 5.59 (s, 1H)， 3.50(s, 2H) , 1.34 (s, 9H)。 'H-NMRCCDCls, 400 MHz) δ: 7.89-7.91 (m, 2H), 7.51-7.55 (m, 5H), 5.59 (s, 1H), 3.50 (s, 2H), 1.34 (s, 9H).

中间体 23 Intermediate 23

标题化合物以中间体 1和中间体 6为原料如一般操作 A, 步驟 4所述制备，得白色固体。

The title compound was prepared from Intermediate 1 and Intermediate 6 using mp.

中间体 24 Intermediate 24

标题化合物以中间体 1和中间体 7为原料如一般操作 A, 步驟 4所述制备，得白色固体。 The title compound was prepared using Intermediate 1 and Intermediate 7 as a crude material.

中间体 25 Intermediate 25

标题化合物以中间体 1和中间体 8为原料如一般操作 A, 步驟 4所迷制备，得白色固体。 The title compound was prepared from Intermediate 1 and Intermediate 8 as mp.

^-NM C CDC1₃, 400MHz ) δ: 7.44 (d, 2H, /=8.4 Hz)， 7.29 (d, 2H， 7=8.4 Hz), 5.51(s, 1H), 3.72 (s, 2H)， 2.93 (m, 1H), 1.31 (s 9H), 1.25 (d, 3H)， 1.24 (d, 3H)。 ^-NM C CDC1 ₃ , 400MHz ) δ: 7.44 (d, 2H, /=8.4 Hz), 7.29 (d, 2H, 7=8.4 Hz), 5.51(s, 1H), 3.72 (s, 2H), 2.93 (m, 1H), 1.31 (s 9H), 1.25 (d, 3H), 1.24 (d, 3H).

中间体 26

Intermediate 26

标题化合物以中间体 1和中间体 9为原料如一般操作 A, 步骤 4所述制备，得白色固体。 The title compound was prepared as a starting material from Intermediate 1 and Intermediate 9 as mp.

-爾 R( CDC1₃, 400MHz ) δ: 7.77 (d, 2H, /=8.4 Hz)， 7.69 (d, 2H, /=8.4 Hz) , 5.56 (s, 1H), 3.76 (s, 2H)， 1.31 (s， 9H)。 -R (CDC1 ₃ , 400MHz ) δ: 7.77 (d, 2H, /=8.4 Hz), 7.69 (d, 2H, /=8.4 Hz), 5.56 (s, 1H), 3.76 (s, 2H), 1.31 (s, 9H).

中间体 27 Intermediate 27

标题化合物以中间体 1和中间体 10为原料如 The title compound is based on intermediate 1 and intermediate 10 as

中间体 28

在 50mL 圆底瓶中加入特戊酰基乙腈（中间体 1 ) l.²⁵g ( 0. Olmol )，氢氧化钠 ( 0.84g， 0.021mol )以及水 10mL, 搅拌，加热到 50Ό, 分批加入盐酸羟胺（ 0.76g， 0. Ollmol) 。加完后升温到 100"Ό，反应 4小时，冷却，乙酸乙酯提取，干燥，柱分离，得白色片状固体 1.23g, 收率 88.0%。 ^XH-NMR (CDCls, 400MHz ) δ: 5.03 (s, 1H) , 4.32 (s, 2H) 1.27(s, 9H)。由 α -氯代酮制备 1， 3-二取代 -4-氨基吡唑类的一般操作 B Intermediate 28

Add pivaloyl acetonitrile (intermediate 1) l. ²⁵ g (0. Olmol), sodium hydroxide (0.84 g, 0.021 mol) and water 10 mL in a 50 mL round bottom flask, stir, heat to 50 Ό, add hydrochloric acid in batches. Hydroxylamine (0.76 g, 0. Ollmol). After the completion of the addition, the mixture was heated to 100 Torr, and reacted for 4 hours, cooled, extracted with ethyl acetate, dried, and then purified to afford white crystals of 1.23 g. ^X H-NMR (CDCls, 400 MHz) δ: 5.03 (s, 1H), 4.32 (s, 2H) 1.27 (s, 9H). General procedure for the preparation of 1, 3-disubstituted-4-aminopyrazoles from α-chloroketones

1. a-氯代酮（ 0. Olmol )溶于 lOmLDMF, 加入邻苯二甲酰亚胺鉀盐（ 0. Olmol )， 70Ό反应 2小时，冷却，倒到 lOOmL水水中，析出白色固体，过滤，干燥得到产品。 1. a-chloroketone (0. Olmol) dissolved in 10 mL of DMF, added potassium phthalimide (0.0.molol), 70 Ό reaction for 2 hours, cooled, poured into 100 mL of water, a white solid precipitated, filtered , dry to get the product.

2. 步驟 1得到的产品（ 0. Olmol )溶于 20mL DMF, 滴加 N, N -二甲基甲酰胺二甲基缩醛（1.44g, 0.012mol)， 100 反应 12 小时，补加 N, N -二甲基甲酰胺二甲基缩醛（1.44g， 0.012mol) , 继续反应 24小时，冷却，倒到 lOOmL冰水中，乙酸乙酯提取，干燥，柱分离，得到白色固体产品。 2. The product obtained in step 1 (0. Olmol) was dissolved in 20 mL of DMF, N,N-dimethylformamide dimethyl acetal (1.44 g, 0.012 mol) was added dropwise, 100 was reacted for 12 hours, and N was added. N-Dimethylformamide dimethyl acetal (1.44 g, 0.012 mol) was further reacted for 24 hours, cooled, poured into 100 mL of ice water, extracted with ethyl acetate, dried and then purified to afford white solid.

3. 步骤 2得到的产品（0. Olmol)溶于 lOOmL 90%乙醇，加入取代的肼（0. Ollmol) , 加热回流 12小时，冷却，析出固体，过滤，滤饼用无水***洗涤，干燥得到白色固体产品。 3. The product obtained in step 2 (0. Olmol) is dissolved in 100 mL of 90% ethanol, substituted hydrazine (0. Ollmol) is added, heated under reflux for 12 hours, cooled, solid is precipitated, filtered, and the filter cake is washed with anhydrous diethyl ether and dried. A white solid product was obtained.

4. 步驟 3得到的产品（ 0. Olmol )溶于 lOOmL 乙醇，滴加 85%的水合肼溶液（0.04mol) , 加热回流 2小时，析出白色固体，冷却，浓缩，加入 20mL***，过滤，滤饼用无水***洗涤，合并滤液，浓缩，柱分离，得到白色粉末状产品。中间体 29

4. The product obtained in step 3 (0. Olmol) was dissolved in 100 mL of ethanol, 85% hydrazine hydrate solution (0.04 mol) was added dropwise, and heated under reflux for 2 hours to precipitate a white solid, which was cooled, concentrated, and then added with 20 mL of diethyl ether, filtered and filtered. The cake was washed with anhydrous diethyl ether, and the filtrate was combined, concentrated, and purified to afford white powder. Intermediate 29

无水三氯化铝（ 5. 60g， 0. 04mol ) 悬浮于 40mL无水甲苯中，搅拌，室温下慢慢滴加氯乙酰氯（4. 52g， 0. 04mol ) , 三氯化铝逐渐溶解，慢慢升温到 80°C反应 2小时，冷却，倒入 100g碎冰和 lOfflL浓盐酸形成的溶液中，分液，水层用甲苯提取三次，合并甲苯层，依次用 10%氢氧化钠，水，饱和食盐水洗涤，干燥，柱分离，得到产品，收率 86. 3%。 Anhydrous aluminum trichloride (5.60 g, 0.04 mol) was suspended in 40 mL of anhydrous toluene, stirred, and chloroacetyl chloride (4.52 g, 0.04 mol) was slowly added dropwise at room temperature, and aluminum trichloride was gradually dissolved. The temperature was slowly raised to 80 ° C for 2 hours, cooled, poured into a solution of 100 g of crushed ice and lOfflL concentrated hydrochloric acid, separated, and the aqueous layer was extracted three times with toluene, and the toluene layer was combined, followed by 10% sodium hydroxide. 3%。 The water, the saturated brine was washed, dried, column separation, the product was obtained, the yield was 86.3%.

中间体 30

Intermediate 30

标题化合物以中间体 29 和邻苯二甲酰亚胺钾盐为原料如一 The title compound is based on intermediate 29 and potassium phthalimide as a raw material.

.作 B, 步骤 1所述制备，得白色固体，收率 87. 8%。 8%。 The yield of the white solid, a yield of 87.8%.

'H-NMR ( CDC1₃, 400MHz ) δ : 7. 88-7. 91 (m, 4H) , 7. 76 (m,'H-NMR (CDC1 ₃ , 400MHz ) δ : 7. 88-7. 91 (m, 4H) , 7. 76 (m,

7. 30-7. 32 (m, 2H) , 5. 51 (s， 2H)， 2. 44 (s, 3H)。 7. 30-7. 32 (m, 2H) , 5. 51 (s, 2H), 2. 44 (s, 3H).

中间体 31

Intermediate 31

标题化合物以中间体 30为原料如一般操作 B, 步驟 2所述制备，得白色固体，收率 61. 5%。 5%。 The title compound was obtained as a white solid, a yield of 61.5%.

中间体 32

Intermediate 32

标题化合物以中间体 31为原料如一般操作 B, 步驟 3所述制备，得白色固体，收率 72.3%。 The title compound was obtained from Intermediate 31 (m.p.

中间体 33 Intermediate 33

标题化合物以中间体 32为原料如一般操作 B，步骤 4所述制备，得白色固体，收率 82.6%。 The title compound was obtained from Intermediate 32 using mp.

H-NMR ( CDC1₃, 400MHz ) δ: 7.21-7.26 (m, 5H)， 2.68 (s, 2H)， 2.41(s, 3H)， 1.41 (s, 9H)。 H-NMR (CDC1 ₃ , 400MHz) δ: 7.21-7.26 (m, 5H), 2.68 (s, 2H), 2.41 (s, 3H), 1.41 (s, 9H).

由 α -氯代酮制备 1， 4-二取代 -2-氨基咪唑类的一般操作 C General procedure for the preparation of 1, 4-disubstituted-2-aminoimidazoles from α-chloroketones C

1. a-氯代酮（ 0.012mol )与芳胺 ( 0. Olmol )溶于 20mLDMF, 加入碳酸氢钠（1.26g， 0.015mol) , 75Ό反应 48小时，冷却，倒入 lOOmL水水中，析出固体，过滤，干燥得到产品。收率 99.2%。 1. a-chloroketone (0.012 mol) and aromatic amine (0.0.molol) dissolved in 20mL DMF, added sodium bicarbonate (1.26g, 0.015mol), 75Ό reaction for 48 hours, cooled, poured into 100mL water, precipitated solid , filtered, dried to give the product. The yield was 99.2%.

2. 步驟 1得到的产品（0, Olmol)，氰胺（4.23g， 0. lOmol ) 在 100mL乙醇中回流 12小时。浓缩，残余物加入水，用乙酸乙酯提取三次，合并有机层，依次用稀氢氧化钠溶液，水，饱和食盐水洗涤，干燥，柱分雋得到白色固体产品。 2. The product obtained in step 1 (0, Olmol), cyanamide (4.23 g, 0.1 mol) was refluxed in 100 mL of ethanol for 12 hours. Concentrate, add the residue to water, extract three times with ethyl acetate, combine the organic layer, then dilute sodium hydroxide solution, water, saturated salt Water washing, drying, and column separation gave a white solid product.

中间体 34 Intermediate 34

标题化合物以对甲基苯胺和特戊酰基曱基氯为原料如一般操作 C，步骤 1所述制备，得白色固体，收率 99. 2%。 The title compound is obtained as a white solid in a yield of 99.2%.

中间体 35 Intermediate 35

标题化合物以中间体 35为原料如一般操作 C，步驟 1所述制备，得白色固体，收率 56. 7%。 7%。 The title compound was obtained as a white solid, a yield of 56.7%.

^- MR ( CDC1₃, 400MHz ) δ : 7. 26 (m, 4H) , 6. 35 (s, 1H)， 4. 18 (s, 2H)， 2. 39 (s, 3H)， 1. 27 (s, 9H)。 ^- MR ( CDC1 ₃ , 400MHz ) δ : 7. 26 (m, 4H) , 6. 35 (s, 1H), 4. 18 (s, 2H), 2. 39 (s, 3H), 1. 27 (s, 9H).

P - L-Ar₂NH₂根据结构的不同，可以由以下路线合成。 P - L-Ar ₂ NH ₂ can be synthesized by the following route depending on the structure.

1. 8-氨基- 5-甲氧基色烯的合成。 1. Synthesis of 8-amino-5-methoxy chromene.

( 1 ) 3 -甲氧基苯酚（ 4· 96g, 0.04mol )溶于 50mL丙酸，冷却至- 10°C, 滴加 0.5 mL 丙酸酐，分 4比加入亚硝酸钠（2.90g， 0.042mol ) ，析出棕色固体，反应 1小时，倒入 250mL水水中，过滤，水洗，干燥得到 4.03g中间体 36，为棕黄色固体。 (1) 3-methoxyphenol (4.66 g, 0.04 mol) was dissolved in 50 mL of propionic acid, cooled to -10 °C, 0.5 mL of propionic anhydride was added dropwise, and sodium nitrite (2.90 g, 0.042 mol) was added in 4 portions. The brown solid was precipitated, and the mixture was reacted for 1 hour, poured into water (250 mL), filtered, washed with water and dried to give 4.03 g of Intermediate 36 as a brown solid.

( 2 ) 中间体 36 ( 1.53g， 0. Olmol )溶于 16mL丙酸，冷却至 -12°C, 滴加发烟硝酸（1.26g, 0.02mol ) , 搅拌 2 小时，倒入 50mL冰水中，析出固体，过滤，水洗，干燥得到 1.38g中间体 37, 为棕黄色固体，收率 77.4%。 (2) Intermediate 36 (1.53 g, 0. Olmol) was dissolved in 16 mL of propionic acid, cooled to -12 ° C, and fuming nitric acid (1.26 g, 0.02 mol) was added dropwise, stirred for 2 hours, and poured into 50 mL of ice water. The solid was precipitated, filtered, washed with water and dried to afford 1.38 g of Intermediate 37 as a brown solid.

( 3) 中间体 37 (1.69g， 0. Olmol)溶于 15mLDMF,加入 3 -溴丙炔（1.43g, 0.012mol ) , 70Ό反应 6小时，冷却，倒入冰水中，析出土黄色固体，过滤，洗涤，干躁，得到 1.87 g 中间体 38，为棕黄色固体，收率 90.3°/。。 (4) 中间体 38 ( 8.46g， 0.041mol )溶于 88mL N，N-二乙基苯胺，加热到 180-210Ό反应 1-6小时，冷却，倒入 500mL冷稀盐酸中，过滤，滤液用乙酸乙酯提取三次，合并乙酸乙酯层，饱和食盐水洗，干燥，柱分离得到 1.84g中间体 39，为黄色固体，收率 21.8°/。。 (3) Intermediate 37 (1.69g, 0. Olmol) was dissolved in 15mL of DMF, added with 3-bromopropyne (1.43g, 0.012mol), 70Ό reaction for 6 hours, cooled, poured into ice water, precipitated a yellow solid, filtered , washed, dried, to give 1.87 g of Intermediate 38 as a tan solid. . (4) Intermediate 38 ( 8.46g, 0.041mol) dissolved in 88mL N,N-diethylaniline, heated to 180-210Ό for 1-6 hours, cooled, poured into 500mL cold dilute hydrochloric acid, filtered, filtrate The ethyl acetate was extracted three times, and the ethyl acetate layer was combined, washed with brine, dried .

(5)中间体 39 ( 1.24g, 6mmol )溶于 5 OmL乙酸乙酯和 5 OmL 乙醇，分批加入二水合氯化亚锡（5.41g, 24mmol ) , 反应液变混浊，加热回流 8小时，冷却，加入饱和碳酸氢钠溶液，直至出现明显分层，分液，水层用乙酸乙酯提取 2次，合并有机层，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩，柱分离得到 0.64g 中间体 40, 收率 59.9%o (5) Intermediate 39 (1. 24 g, 6 mmol) was dissolved in ethyl acetate (5 mL) and ethyl acetate (50 mL), and then stannous chloride (5.41 g, 24 mmol) was added in portions. The reaction mixture became cloudy and heated to reflux for 8 hours. After cooling, a saturated aqueous solution of sodium hydrogencarbonate was added, and the mixture was separated, and the mixture was separated, and the aqueous layer was extracted twice with ethyl acetate. The organic layer was combined, washed with brine, dried over anhydrous sodium sulfate, filtered, 0.64 g of intermediate 40 was obtained in a yield of 59.9%.

( 6 ) 中间体 39 ( 1.04g， 0.005mol )溶于 50mL无水乙醇，假如 0.2g钯 /炭，升温到 70V, 滴加 1. OmL水合肼（ 85%) ，升温回流 4小时，冷却，过滤，滤液干燥，浓缩得到 0.62g中间体 41, 收率 72.5%。 (6) Intermediate 39 (1.04 g, 0.005 mol) was dissolved in 50 mL of absolute ethanol, if 0.2 g of palladium on charcoal, the temperature was raised to 70 V, 1.0 mL of hydrazine hydrate (85%) was added dropwise, and the mixture was heated to reflux for 4 hours, and cooled. Filtration, the filtrate was dried and concentrated to give <RTIgt;

2. 8-氨基 -3， 4-二氢 -5-取代烷氧基- 2 色烯。 P 的定义同通式 I。 2. 8-Amino-3,4-dihydro-5-substituted alkoxy-2 chromene. P is defined as the formula I.

48 49 XXIV XXV 48 49 XXIV XXV

( 1 ) 间苯二酚（ 44. Og, 0.40mol )溶于 150mLDMF，加入无水碳酸钾（ 66.24g， 0.48mol ) ，水水浴冷却下滴加溴苄（ 47.88g， 0.28mol ) , 加毕反应 5小时，倒入冷稀盐酸中，使显酸性，乙酸乙酯提取三次，合并乙酸乙酯层，饱和食盐水洗，干燥，柱分离得到 26.25g 中间体 42，为无色油状物，放置后变为白色固体，收率 46.9%。 (1) Resorcinol (44. Og, 0.40 mol) was dissolved in 150 mL of DMF, anhydrous potassium carbonate (66.24 g, 0.48 mol) was added, and benzyl bromide (47.88 g, 0.28 mol) was added dropwise with cooling in a water bath. The reaction was carried out for 5 hours, poured into cold dilute hydrochloric acid to make acidity, and extracted with ethyl acetate three times. The ethyl acetate layer was combined, washed with saturated brine, and dried. It turned into a white solid with a yield of 46.9%.

(2) 中间体 43以中间体 42为原料，按照合成中间体 37的方法制备，为棕色固体，收率 74.1%。 (2) Intermediate 43 is based on the intermediate 42 as the synthesis intermediate 37 The method was prepared as a brown solid with a yield of 74.1%.

( 3 ) 中间体 44以中间体 43为原料，按照合成中间体 38的方法制备，为棕色固体，收率 89.0%。 (3) Intermediate 44 was prepared from Intermediate 43 using mp.

(4) 中间体 45以中间体 44为原料，按照合成中间体 39的方法制备，为棕色固体，收率 95.0%。 (4) Intermediate 45 was obtained from Intermediate 44 (yield: mp.

(5) 中间体 46以中间体 45为原料，按照合成中间体 40的方法制备，为黄色固体，收率 20- 25%。 (5) Intermediate 46 was prepared as Intermediate 7 using Intermediate 45 as a yellow solid. Yield: 20-25%.

(6) 5. Og中间体 46溶于 lOOmL无水乙醇，滴加 2滴盐酸，加入 2.0g钯 /炭，加热至 60°C, 滴加 10. OmL水合肼（85%) , 升温回流 6小时'，冷却，过滤，滤液干燥，浓缩，残余物溶于 lOOmL 二氯甲烷，加入 3. OmL三乙胺，水水浴冷却，滴加 4.0 g(Boc)₂0，然后室温反应过夜，倒入水中，二氯甲烷提取，干燥，柱分离得到 1.69g中间体 48，为白色粉末状固体。 (6) 5. Og intermediate 46 is dissolved in 100 mL of absolute ethanol, 2 drops of hydrochloric acid is added dropwise, 2.0 g of palladium on charcoal is added, heated to 60 ° C, and 10. OmL of hydrazine hydrate (85%) is added dropwise, and the temperature is refluxed. h ', cooled, filtered, the filtrate was dried, concentrated, and the residue was dissolved in lOOmL of dichloromethane, was added triethylamine 3. OmL, water-water bath was added dropwise 4.0 g (Boc) ₂ 0, then room temperature overnight, poured into In water, dichloromethane was extracted, dried, and then purified to give white crystals.

(7)中间体 48( 2.20g， 8.3mmol )溶于 50mL乙腈，加入 1.37 g无水碳酸钾，滴加 1, 2-二溴丙烷（ 6.23g， 33mmol ) , 加热回流 72小时，浓缩，残余物加入 30mL水，乙酸乙酯提取三次，合并乙酸乙酯层，饱和食盐水洗，干燥，柱分离得到 0.83g中间体 49, 并且回收原料 1.61g。 (7) Intermediate 48 ( 2.20 g, 8.3 mmol) was dissolved in 50 mL of acetonitrile, 1.37 g of anhydrous potassium carbonate was added, and 1,2-dibromopropane ( 6.23 g, 33 mmol) was added dropwise, heated under reflux for 72 hours, concentrated, residue After adding 30 mL of water, ethyl acetate was extracted three times, and the ethyl acetate layer was combined, washed with saturated brine, dried, and the column was separated to obtain 0.83 g of intermediate 49, and 1.61 g of the starting material was recovered.

(8)合成中间体 XX V的一般操作 C。 (8) General procedure for the synthesis of intermediates XX V C.

a.中间体 49 ( 1.86g, 5mmol ) 溶于 2 OmL DMF，加入 0.83g无水碳酸钾，加入1^(611111101),80°(反应 1-6小时，冷却，倒入冷水中，乙酸乙酯提取，干燥，柱分离得到化合物 XX IV。 a. Intermediate 49 ( 1.86 g, 5 mmol) dissolved in 2 mL of DMF, added 0.83 g of anhydrous potassium carbonate, added 1 ^ (611111101), 80 ° (reaction 1-6 hours, cooled, poured into cold water, acetic acid B Ester extraction, drying, column separation gave compound XX IV.

b. 化合物 XXIV (2mmol) 溶于 20mL二氯甲烷，冷却至 - 5Ό，滴加 2. OmL三氟乙酸，反应 2小时，浓缩，残余物加入 3 OmL水，用 1N氢氧化钠调到 _PH 10，乙酸乙酯提取，干燥，浓缩，得到 X XV的粗品，不纯化，直接用于下一步的反应。 b. Compound XXIV (2mmol) was dissolved in 20mL of dichloromethane, cooled to -5 Ό, added dropwise with 2. OmL of trifluoroacetic acid, reacted for 2 hours, concentrated, and the residue was added to 3OmL of water and adjusted to _P H with 1N sodium hydroxide. 10, ethyl acetate was extracted, dried and concentrated to give a crude product of X XV, which was used in the next step without purification.

中间体 50

Intermediate 50

标题化合物以中间体 49和***啉为原料如一般操作 C所迷制 The title compound is prepared from the intermediate 49 and morpholine as a general operation C.

标题化合物以中间体 49和 4-哌啶酮为原料如一般操作 C所述制备 o The title compound is prepared from the intermediate 49 and 4-piperidinone as described in General Procedure C.

中间体 52 Intermediate 52

标题化合物以中间体 49和咪唑为原料如一般操作 C所述制中间体 53 The title compound is prepared from intermediate 49 and imidazole as described in General Procedure C.

标题化合物以中间体 49和 1， 2 , 4-三氮唑为原料如一般操作 C所述制备。

The title compound was prepared from Intermediate 49 and 1,2,4-triazole as described in General Procedure C.

中间体 54 Intermediate 54

标题化合物以中间体 49和吡唑为原料如一般操作 C所述制中间体 55

The title compound is prepared from intermediate 49 and pyrazole as intermediate C as described in General Procedure C.

标题化合物以中间体 49和顺式 -2, 6-二甲基***啉为原料如一般操作 C所述制备。 The title compound was prepared using Intermediate 49 and cis -2,6-dimethylmorpholine as described in General Procedure C.

中间体 56 Intermediate 56

标题化合物以中间体 49和 4-羟基吡啶为原料如一般操作 C 所述制备。 The title compound was prepared using Intermediate 49 and 4-hydroxypyridine as starting material.

中间体 57

Intermediate 57

48 57 58 中间体 48 ( 1, 59g， 6mmol )溶于 50 mL无水四氢呋喃，加入 4- ( 2-羟基乙基）吡啶（616 mg, 5 mmol ) , 三苯基磷（ 1. 57g, 5 mmol )和 DEAD ( 1. 05g, 5 mmol )，加热回流 3小时，反应完成。柱分离得到 1. 76g中间体 57 , 收率 95. 0%。 48 57 58 Intermediate 48 (1,59 g, 6 mmol) dissolved in 50 mL anhydrous tetrahydrofuran, 4-(2-hydroxyethyl)pyridine (616 mg, 5 mmol), triphenylphosphine ( 1. 57 g, 5 Methyl) and DEAD (1.05 g, 5 mmol) were heated to reflux for 3 hours and the reaction was completed. The yield was 95. 0%.

中间体 58 Intermediate 58

标题化合物以中间体 57为原料如一般操作 C 步驟 b所述制备。 The title compound is prepared from Intermediate 57 as described in General Procedure C, step b.

标题化合物以中间体 48和 4- ( 2-氯乙酰基）吡啶为原料如一般操作 C所述制备。 The title compound was prepared from Intermediate 48 and 4-(2-chloroacetyl)pyridine as described in General Procedure C.

3. 8 -氨基 -5-取代烷氧基- 2^色烯。 P的定义同通式 I。 3. 8-Amino-5-substituted alkoxy-2 chromene. P is defined as the formula I.

⁶³ 64 XXVI XXW ⁶³ 64 XXVI XXW

(1) 中间体 45 ( 70.83g, 0.25mol )溶于 300mL乙酸乙酯，加入 300mL氢溴酸，加热回流 8小时，减压蒸馏，残余物柱分离得到 31. l 中间体 60, 为红棕色固体，收率 64.4%。 (1) Intermediate 45 (70.83g, 0.25mol) dissolved in 300mL of ethyl acetate, added 300mL of hydrobromic acid, heated under reflux for 8 hours, distilled under reduced pressure, and the residue was separated to give 31. l Intermediate 60, reddish brown Solid, yield 64.4%.

( 2 ) 中间体 60 ( 38.26g, 0.198mol )溶于 200mL DMF，加入无水碳酸钾（ 32.84g， 0.24mol ) , 加入对甲氧基氯苄（6腿 ol)，室温反 8小时，倒入冷水中，析出棕黄色固体，过滤，干蜾，得到 58.96 中间体 61，收率 95.0%。 (2) Intermediate 60 (38.26g, 0.198mol) was dissolved in 200mL DMF, anhydrous potassium carbonate (32.84g, 0.24mol) was added, p-methoxybenzyl chloride (6 leg ol) was added, and the temperature was reversed for 8 hours at room temperature. Into cold water, a brown solid was precipitated, which was filtered and dried to give 58.96 Intermediate 61, yield 95.0%.

(3) 以中间体 61为原料，采用中间体 46的制备方法，得到黄色的中间体 62, 收率 20-45%。 (3) Using Intermediate 61 as a raw material, using Intermediate 46, a yellow intermediate 62 was obtained in a yield of 20-45%.

( 4 ) 中间体 61 ( 18.2g， 0.058mol )溶于 150mL二氯甲烷，冷却到 - 10Ό，滴加 10. OmL三氟乙酸，反应 8小时，浓缩，残余物加入 50mL水，用 IN氢氧化钠调到 pH 10，乙酸乙酯提取，干燥，浓缩，柱分离得到 7.5g中间体 63，为黄色固体。 (4) Intermediate 61 ( 18.2 g, 0.058 mol) was dissolved in 150 mL of dichloromethane, cooled to - 10 Ό, dropwise. The sodium was adjusted to pH 10, extracted with ethyl acetate, dried and concentrated.

(5) 中间体 63 ( 5.97g, 31mmol) 溶于 150mL 乙腈，加入 5.13 g无水碳酸钟，滴加 1， 2-二溴丙烷（ 23.23g， 124mmol ) , 加热回流 2.5小时，浓缩，残余物加入 50mL水，乙酸乙酯提取三次，合并乙酸乙酯层，饱和食盐水洗，干燥，柱分离得到 4.69g 中间体 64，为黄色固体，收率 34.4%。 (5) Intermediate 63 ( 5.97 g, 31 mmol) was dissolved in 150 mL of acetonitrile, 5.13 g of anhydrous carbonic acid was added, and 1,2-dibromopropane ( 23.23 g, 124 mmol) was added dropwise. The mixture was heated to reflux for 2.5 hr. EtOAc (EtOAc m.

(6)合成中间体 XX VII的一般操作 D。 (6) General procedure for the synthesis of intermediates XX VII D.

a.中间体 64 ( 1.50g, 5讓 ol )溶于 20mL DMF，加入 0, 83g无 7j碳酸钟，加入 ΗΡ(6πιοιο1)，80Χ反应 2-6小时，冷却，倒入冷水中，乙酸乙酯提取，干燥，柱分离得到化合物 XXVI。 a. Intermediate 64 (150g, 5 let ol) dissolved in 20mL DMF, add 0, 83g without 7j carbonic acid clock, add ΗΡ (6πιοιο1), 80Χ reaction for 2-6 hours, cool, pour into cold water, ethyl acetate Extraction, drying, column separation gave compound XXVI.

b. 化合物 ¥1(5!1111101)溶于 501^乙酸乙酯和 50mL乙醇，分批加入二水合氯化亚锡（4.50g， 20mmol )，反应液变混浊，加热回流 8小时，冷却，加入饱和碳酸氢钠溶液，直至出现明显分层，分液，水层用乙酸乙酯提取 2次，合并有机层，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得到化合物 XXVII，收率 85-95%。不纯化，直接用于下一步的反应。 b. Compound ¥1 (5!1111101) was dissolved in 501 ethyl acetate and 50 mL ethanol, and stannous chloride dihydrate (4.50 g, 20 mmol) was added portionwise. The reaction mixture became cloudy, heated under reflux for 8 hours, cooled, and added. Saturated sodium bicarbonate solution, until viscous stratification, liquid separation, the aqueous layer was extracted twice with ethyl acetate, and the organic layer was combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give compound XXVII, yield 85-95%. Not purified, used directly in the next reaction.

中间体 65 Intermediate 65

标题化合物以中间体 64和***啉为原料如一般操作 D所述制备。 The title compound was prepared from the intermediate 64 and morpholine as described in general procedure D.

中间体 66 Intermediate 66

标题化合物以中间体 64和顺式 -2, 6-二甲基***啉为原料如一般操作 D所述制备。 The title compound is based on intermediate 64 and cis-2,6-dimethylmorpholine. Prepared as described in General Procedure D.

中间体 67

Intermediate 67

标题化合物以中间体 64和 4-羟基吡啶为原料如一般操作 D 所述制备。 The title compound was prepared using Intermediate 64 and 4-hydroxypyridine as starting material.

中间体 68 Intermediate 68

标题化合物以中间体 63和 4 （ 2-氯乙酰基）吡啶为原料如一般操作 D所述制备。 The title compound was prepared using the intermediates 63 and 4 (2-chloroacetyl)pyridine as described in general procedure D.

中间体 69 Intermediate 69

标题化合物以中间体 64和 1， 2， 4-三氮唑为原料如一般操作 D 所述制备。 The title compound was prepared starting from intermediate 64 and 1,2,4-triazole as described in general procedure D.

中间体 70 Intermediate 70

标题化合物以中间体 64和 4-哌啶酮为原料如一般操作 D所述制备。 4. 8-氨基 -5-取代氨基色烯。 The title compound was prepared from Intermediate 64 and 4-piperidinone as described in General Procedure D. 4. 8-Amino-5-substituted aminochromene.

74 75 76 74 75 76

( 1 ) 2 -氨基 -5 -硝基苯酚（ 46.2g, 0.30mol )溶于 300mL二氯甲烷，冷却至 - 5°C, 加入三乙胺（36.3g, 0.33mol) ，搅拌下滴加 (Boc)₂0 (72.0g,0.33mol),然后加热回流 6小时。冷却，倒入 500mL 水中，分液，水层用二氯甲烷提取 2次，合并有机层，饱和食盐水洗涤，无水疏酸钠干燥，浓缩得到中间体 71, 为黄色粘稠的固体。 (1) 2 -Amino-5-nitrophenol (46.2 g, 0.30 mol) was dissolved in 300 mL of dichloromethane, cooled to - 5 ° C, triethylamine (36.3 g, 0.33 mol) was added and added dropwise with stirring ( Boc) ₂ 0 (72.0 g, 0.33 mol), then heated to reflux for 6 hours. After cooling, it was poured into 500 mL of water, and the mixture was separated. The aqueous layer was extracted twice with methylene chloride. The organic layer was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to afford intermediate 71 as yellow viscous solid.

(2) 上步得到的中间体 71 溶于 200fflL DMF，加入无水碳酸钾 ( 41.4g, 0.30mol )和 3-溴丙炔 ( 35.7g， 0.30mol )，加热至 70 (2) Intermediate 71 obtained in the above step was dissolved in 200fflL DMF, anhydrous potassium carbonate (41.4 g, 0.30 mol) and 3-bromopropyne (35.7 g, 0.30 mol) were added and heated to 70

°C反应 8小时，冷却，倒入水中，析出黄色固体，乙酸乙酯 /石油醚重结晶得到 30.5g中间体 72。 The mixture was reacted for 8 hours, cooled, poured into water to give a yellow solid, and ethyl acetate / petroleum ether.

(3) 中间体 72 (15.32g)溶于 lOOmL N，N-二乙基苯胺，加热到 180°C反应 4 小时，减压蒸馏，除去溶剂，残余物经柱分离得到 7.94 中间体 73, 为黄色固体，收率 78.8%。 (3) Intermediate 72 (15.32g) was dissolved in 100 mL of N,N-diethylaniline, heated to 180 ° C for 4 hours, distilled under reduced pressure, solvent was removed, and the residue was purified by column to give 7. Yellow solid, yield 78.8%.

(4) 中间体 73 ( 1.92g, lOmmol )溶于 30mL二氯甲烷，冷却至 - ，加入三乙胺（ 1.21g, llramol ),搅拌下滴加氯乙酰氯（ 1.24g， llmmol) , 回流 24小时，冷却，倒入水中，二氯甲烷提取，干燥，柱分离得到 1.53g中间体 74, 为黄色固体，收率 57.3%。 ( 5 )中间体 74 ( 1.34g, 5mmol )溶于 lOmL DMF,加入无水碳酸钟 ( 0.83g, 6mmol )和***啉（ 0.52g, 6mmol ) , 80°C反应 4小时，倒入水中，乙酸乙酯提取，干燥，柱分离得到 1.48g中间体 75，为黄色固体，收率 92.7°/。。 (4) Intermediate 73 ( 1.92 g, 10 mmol) was dissolved in dichloromethane (30 mL), cooled to -, triethylamine (1. 21 g, llramol) was added, and chloroacetyl chloride ( 1.24 g, llmmol) was added dropwise with stirring, reflux 24 Hour, cooled, poured into water, extracted with dichloromethane, dried and evaporated tolulu (5) Intermediate 74 (1. 34 g, 5 mmol) was dissolved in 10 mL of DMF, and then anhydrous carbonated (0.83g, 6mmol) and morpholine (0.52g, 6mmol), and reacted at 80 ° C for 4 hours, poured into water, acetic acid Ethyl acetate extraction, drying and column chromatography gave 1.48 g of Intermediate 75 as a yellow solid. .

(6) 中间体 75 ( 640mg, 2mmol )溶于 30mL乙酸乙酯和 30mL乙醇，分批加入二水合氯化亚锡（1.80g， 8mmol )，反应液变混浊，加热回流 8小时，冷却，加入饱和碳酸氢钠溶液，直至出现明显分层，分液，水层用乙酸乙酯提取 2次，合并有机层，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得到 545mg中间体 76，收率 94.3%。不纯化，直接用于下一步的反应。 (6) Intermediate 75 (640 mg, 2 mmol) was dissolved in 30 mL of ethyl acetate and 30 mL of ethanol, and stannous chloride dihydrate (1.80 g, 8 mmol) was added in portions. The reaction mixture became cloudy, heated under reflux for 8 hours, cooled, and added. Saturated sodium bicarbonate solution, until viscous stratified, partitioned, and the aqueous layer was extracted twice with ethyl acetate. The organic layer was combined, washed with brine, dried over anhydrous sodium sulfate, filtered, The yield was 94.3%. Not purified, used directly in the next reaction.

5. 5-氨基 -8-取代氨基色烯。 5. 5-Amino-8-substituted aminochromene.

77 78 79

77 78 79

80 81 80 81

(1) 中间体 73 ( 1.92g, lOmmol)溶于 30mL二氯甲烷，冷却至 0 Ό, 加入三乙胺（1.21g， llmfflol) , 搅拌下滴加（Boc) ₂0 ( 2.38g， llmmol) , 回流 48小时，冷却，倒入水中，二氯甲烷提取，干燥，柱分离得到 1.34g中间体 77, 为黄色固体，收率 45.9%。 ( 2 ) 中间体 77 ( 1. 5g, 5. 14mmol )溶于 50mL 乙醇，加入 0. 3g 钯 /炭，加热至 60Ό，滴加 2. OmL水合肼（ 85% ) , 升温回流 1小时，冷却，过滤，滤液干燥，浓缩，得到 1. 39g中间体 78。 (1) Intermediate 73 (1.92g, lOmmol) was dissolved in 30mL of dichloromethane, cooled to 0 Ό, triethylamine (1.21g, llmfflol), added dropwise with stirring _{(Boc) 2 0 (2.38g,} llmmol) It was refluxed for 48 hours, cooled, poured into water, extracted with methylene chloride, dried and then evaporated. (2) Intermediate 77 (1. 5g, 5. 14mmol) dissolved in 50mL of ethanol, added 0. 3g palladium / carbon, heated to 60 Ό, added dropwise 2. OmL hydrazine hydrate (85%), heated to reflux for 1 hour, cooling The filtrate was dried and concentrated to give 1. 39 g of Intermediate 78.

( 3 )将中间体 78溶于 30mL二氯甲烷，加入 1. 2mL三乙胺，水水浴冷却，滴加氯乙酰氯（ 0. 68g , 6mmol )，反应 2小时，倒入水中，二氯甲烷提取，干燥，柱分离得到 378mg中间体 79，为白色粉末状固体。 (3) Dissolve intermediate 78 in 30 mL of dichloromethane, add 1.2 mL of triethylamine, cool in a water bath, add chloroacetyl chloride (0.68 g, 6 mmol) dropwise, react for 2 hours, pour into water, dichloromethane Extraction, drying and column chromatography gave 378 mg of Intermediate 79 as a white powdery solid.

( 4 ) 中间体 79 ( 534mg , 1. 57mmol )溶于 10mL DMF，加入无水碳酸钾（ 324mg， 2. 35醒 ol ) 和***啉（ 204mg， 2. 35mmol ) , 80 反应 4小时，倒入水中，乙酸乙酯提取，干燥，柱分离得到 313mg 中间体 80, 为白色颗粒状固体，收率 50. 9%。 (4) Intermediate 79 (534 mg, 1. 57 mmol) was dissolved in 10 mL of DMF, and anhydrous potassium carbonate (324 mg, 2.35 awael) and morpholine (204 mg, 2.35 mmol) were added, and the reaction was carried out for 4 hours. 9%。 The water was extracted with EtOAc.

( 5 ) 中间体 80 (313mg， 0. 8mmol) 溶于 30mL二氯甲烷，冷却至 0 °C，滴加 1. 5mL三氟乙酸，反应 4小时，浓缩，残余物加入 3 OmL 水，用 1N氢氧化钠调到 pH 10，乙酸乙酯提取，干燥，浓缩，得到 176mg中间体 81的粗品, 不纯化，直接用于下一步的反应。实施例 (5) Intermediate 80 (313 mg, 0.8 mmol) was dissolved in dichloromethane (30 mL), cooled to 0 ° C, and then evaporated. The sodium hydroxide was adjusted to pH 10, extracted with ethyl acetate, dried and concentrated to give 176 g of crude Intermediate 81. Example

实施例 1 ： 1- [3-叔丁基 -1- (4-甲基苯基）- 1H-5-吡唑基] - 3- [8- (3， 4-二氢 -5-甲氧基 -2 色烯基）]脲 Example 1: 1-[3-tert-Butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3- [8-(3,4-dihydro-5-methoxy) Base-2 alkenyl)]urea

在 50mL三口瓶中加入 20mL干燥的二氯甲烷，冷却到 -10Ό，加入三光气（109mg, 0. 36mmol ) , 滴加 0. 4mL干燥的三乙胺，慢慢滴加中间体 41 ( 180mg, l. Ommol )溶于 10mL干燥二氯曱烷的溶液，反应 1小时。加入中间体 11 ( 138mg , 0. 6mmol ) ，升温至室温，然后加热回流 48小时。冷却，倒入 50mL水中，用二氯甲烷提取 3次，有机层用饱和食盐水洗涤，无水硫酸钠干燥，柱分离（洗脱体系：石油醚 /乙酸乙酯）得到 1- [3-叔丁基 -1- (4-甲基苯基） - 1H-5-吡唑基] - 3- [8- (3， 4-二氢 -5-甲氧基 -2 色烯基） ] 脲 94mg，为白色晶体，收率 21.8%。 Add 20 mL of dry dichloromethane to a 50 mL three-necked flask, cool to -10 Torr, add triphosgene (109 mg, 0.36 mmol), add 0.4 mL of dry triethylamine, and slowly add intermediate 41 (180 mg, l. Ommol) was dissolved in 10 mL of dry dichloromethane solution and allowed to react for 1 hour. Intermediate 11 (138 mg, 0.6 mmol) was added, and the mixture was warmed to room temperature and then evaporated to reflux. The mixture was cooled, poured into 50 mL of water, and extracted with dichloromethane (3××××××××××××××××××××××××××××××××××××××××××××××××××××××××××××× Butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3- [8-(3,4-dihydro-5-methoxy-2-chromenyl)] 94 mg of urea was white crystals with a yield of 21.8%.

'H-NMR ( DMS0, 00ΜΗζ) δ: 8.84 (s, 1H)， 8.30(s, 1H)， 'H-NMR ( DMS0, 00ΜΗζ) δ: 8.84 (s, 1H), 8.30(s, 1H),

7.77(d, IH, 7=8.96 Hz), 7.33~7.37 (m, 4H)， 6.41 (d, 1H，7.77 (d, IH, 7=8.96 Hz), 7.33~7.37 (m, 4H), 6.41 (d, 1H,

/=9.00 Hz), 6.33(s, IH)， 4.14 (t, 2H， /=4.76 Hz), 3.71(s,/=9.00 Hz), 6.33(s, IH), 4.14 (t, 2H, /=4.76 Hz), 3.71(s,

3H), 2.50 (t, 2H)， 2.37 (s, 3H) , 1.88 (p, 2H) , 1.25 (s, 9H)。 3H), 2.50 (t, 2H), 2.37 (s, 3H), 1.88 (p, 2H), 1.25 (s, 9H).

MS (FAB) in/z: 435.1 [M+l〗⁺。实施例 2: 1-[3 叔丁基-卜（4-氯苯基)-1^~5-吡唑基]-3-[8-(5- 甲氧基 2 色烯基)]脲 MS (FAB) in/z: 435.1 [M+l〗 ⁺ . Example 2: 1-[3 tert-butyl-bu(4-chlorophenyl)-1^~5-pyrazolyl]-3-[8-(5-methoxy-2-chromenyl)]urea

采用实施例 1 的制备方法，将其中的中间体 11 改为中间体 15，中间体 41改为中间体 40, 得到标题化合物，为白色固体。 Using the preparation method of Example 1, the intermediate 11 was changed to the intermediate 15 and the intermediate 41 was changed to the intermediate 40 to give the title compound as white solid.

'H-NMR (DMS0, 400ΜΗζ) δ: 8.91 (s, 1H)， 8.31 (s, IH) , 7.82 (d, IH), 7.52 - 7.60 (m， 4H)， 6.65 (d, IH, 7=10.08 Hz), 6.50(d, IH, /=9.28 Hz), 6.36 (s, IH), 5.87 (m, IH), 4.76(t, 2H， /=1.68 Hz), 3.74 (s, 3H) , 1.26(s, 9H)。 'H-NMR (DMS0, 400ΜΗζ) δ: 8.91 (s, 1H), 8.31 (s, IH), 7.82 (d, IH), 7.52 - 7.60 (m, 4H), 6.65 (d, IH, 7=10.08 Hz), 6.50 (d, IH, /=9.28 Hz), 6.36 (s, IH), 5.87 (m, IH), 4.76 (t, 2H, /=1.68 Hz), 3.74 (s, 3H), 1.26 ( s, 9H).

MS (FAB) m/z: 453.0 [M+l]⁺ ₀ MS (FAB) m/z: 453.0 [M+l] ⁺ ₀

'实施例 3 : l-[3-叔丁基 -1- (4-甲基苯基） -IH- 5-吡唑基] - 3- [8- (5 -甲氧基- 2 色烯基) ]脲 'Example 3: l-[3-tert-Butyl-1-(4-methylphenyl)-IH-5-pyrazolyl]-3- [8-(5-methoxy-2 2 alkenyl) ) urea

采用实施例 1 的制备方法，将其中的中间体 41 改为中间体 40，得到标题化合物，为白色固体。 The title compound was obtained as a white solid.

'H-N RCDMSO, 400ΜΗζ) δ 8.83 (s, 1H)， 8.35(s, IH)， 7.81 (d, IH, 7=9.24 Hz) , 7.33— 7.37 (m， 4H)， 6.65(d， IH, /=8.12 Hz)， 6.50 (d, 1H， J=9.24 Hz), 6.33 (s, 1H)， 5.85 (m, IH), 4.75 (t, 2H, 7=1.68 Hz), 3.74 (s, 3H)， 2.37 (s, 3H) , 1.26(s, 9H)。 MS (FAB) m/z: 433.1 [M+l]⁺ ₀ 实施例 4 : 1-[3-叔丁基 - 1- (4-甲基苯基） -1H-5-吡唑基] -3-{5-{8-[2- (4-***啉基）乙酰胺基] 色烯基脲 'HN RCDMSO, 400ΜΗζ) δ 8.83 (s, 1H), 8.35(s, IH), 7.81 (d, IH, 7=9.24 Hz), 7.33— 7.37 (m, 4H), 6.65(d, IH, /= 8.12 Hz), 6.50 (d, 1H, J=9.24 Hz), 6.33 (s, 1H), 5.85 (m, IH), 4.75 (t, 2H, 7=1.68 Hz), 3.74 (s, 3H), 2.37 (s, 3H), 1.26(s, 9H). MS (FAB) m/z: 433.1 [M+l] ⁺ ₀ Example 4: 1-[3-tert-butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{5-{8-[2-(4-morphinolinyl) Acetylamino] chromenyl urea

采用实施例 1 的制备方法，将其中的中间体 41 改为中间体 76，得到标题化合物，为白色固体。 The title compound was obtained as a white solid.

-丽 R (CDC1₃, 400MHz ) δ 9.46(s， 1H)， 7.96 (s, 1H), 7.17-7.26 (m, 4H) , 6.85 (d, 1H)， 6.71 (d, 1H， 7=1.36 Hz)， 6.40 (s, 1H)， 6.36 (d, 1H， 7=10.64 Hz), 5.76 (m, 1H), 4.76 (t, 2H), 3.78 (t, 4H), 3.04 (s, 2H) , 2.62 (t, 4H)， 2.35 (s, 3H)， 1.33(s, 9H)。 -R (CDC1 ₃ , 400MHz ) δ 9.46(s, 1H), 7.96 (s, 1H), 7.17-7.26 (m, 4H) , 6.85 (d, 1H), 6.71 (d, 1H, 7=1.36 Hz ), 6.40 (s, 1H), 6.36 (d, 1H, 7 = 10.64 Hz), 5.76 (m, 1H), 4.76 (t, 2H), 3.78 (t, 4H), 3.04 (s, 2H), 2.62 (t, 4H), 2.35 (s, 3H), 1.33 (s, 9H).

MS (FAB) m/z: 545.1 [M+l]⁺。实施例 5: 1- [3-叔丁基 -1-苯基- 1^-5-吡唑基 ]-3- [8- (3， 4-二氢 -5-曱氧基 - 2 色烯基）]脲 MS (FAB) m/z: 545.1 [M+l] ⁺ . Example 5: 1-[3-tert-Butyl-1-phenyl- 1^-5-pyrazolyl]-3-[8-(3,4-dihydro-5-decyloxy-2-chromene Urea

实施例 2得到的产物 200mg溶于 50mL无水乙醇，加入 0.2g 钯 /炭，加热到 60°C，滴加 1. OmL水合肼，然后加热回流 6小时，冷却，过滤，滤液浓缩，柱分离得到标题化合物 149 mg，为白色固体。 200 mg of the product obtained in Example 2 was dissolved in 50 mL of absolute ethanol, 0.2 g of palladium on charcoal was added, and the mixture was heated to 60 ° C, and 1.0 mL of hydrazine hydrate was added dropwise, followed by heating under reflux for 6 hours, cooled, filtered, and the filtrate was concentrated. The title compound 149 mg was obtained as a white solid.

'H-NMR (CDC1₃, 400MHz ) δ: 7.67 (d, 1H)， 7.32-7.46 (m, 5H), 7.18 (s, 1H)， 6.54 (s, 1H), 6.42 (s, 1H)， 6.35 (d, 1H, 7=8.8 Hz) , 4.08 (t, 2H, 7=8.8 Hz) , 3.79 (s, 3H) , 2.62 (t, 2H， 7=6.8 Hz), 1.92 (p, 2H)， 1.37 (s, 9H)。 'H-NMR (CDC1 ₃ , 400MHz ) δ: 7.67 (d, 1H), 7.32-7.46 (m, 5H), 7.18 (s, 1H), 6.54 (s, 1H), 6.42 (s, 1H), 6.35 (d, 1H, 7=8.8 Hz), 4.08 (t, 2H, 7=8.8 Hz), 3.79 (s, 3H), 2.62 (t, 2H, 7=6.8 Hz), 1.92 (p, 2H), 1.37 (s, 9H).

MS (FAB) m/z: 421.1 [M+l]+。实施例 6 : l-[3-叔丁基 -l-(4-曱基苯基）- 1H-5-吡唑基]- 3-{8-{3， ⁴-二氢 -5- [2- (4-***啉基）乙氧基] -² 色烯基 }} 脲 MS (FAB) m/z: 421.1 [M+l]+. Example 6: l- [3- tert-butyl -l- (4- Yue-yl-phenyl) - 1H-5- pyrazolyl] - 8- {3- {3, ⁴ - dihydro-5- [2 - (4-morphinolinyl)ethoxy] - ² color alkenyl}} Urea

采用实施例 1 的制备方法，将其中的中间体 41 改为中间体 40, 得到标题化合物，为白色固体。 Using the preparation method of Example 1, the intermediate 41 was changed to an intermediate 40, the title compound was obtained as a white solid.

^- MR ( CDCI3, 400MHz ) δ： 7.69 (d, 1H, /=8.4 Hz), 7.29-7.31 (m, 3H), 7.16 (m, 2H) , 6.84 (s, 1H)， 6.31-6.34 (m, 2H), 4.04 - 4.07 (m， 4H) , 3.72 (t, 4H)， 2.80(t, 2H， 7=5.2 Hz), 2.60 (t, 2H), 2.59(t, 4H) , 2.31 (s, 3H) , 1.91 (p, 2H) , 1.34 (s, 9H)。 ^- MR (CDCI3, 400MHz) δ: 7.69 (d, 1H, /=8.4 Hz), 7.29-7.31 (m, 3H), 7.16 (m, 2H), 6.84 (s, 1H), 6.31-6.34 (m , 2H), 4.04 - 4.07 (m, 4H), 3.72 (t, 4H), 2.80(t, 2H, 7=5.2 Hz), 2.60 (t, 2H), 2.59(t, 4H), 2.31 (s, 3H), 1.91 (p, 2H), 1.34 (s, 9H).

MS (FAB) ffl/z: 534.2 [M+l]⁺ ₀ 实施例 7 : 1 - [3-叔丁基 - 1 (4-甲基苯基） -1H- 5-吡唑基] -3- [8- (5-硝基- 2 色烯基） ]脲 MS (FAB) ffl/z: 534.2 [M+l] ⁺ ₀ Example 7: 1 - [3-tert-butyl-1(4-methylphenyl)-1H 5-pyrazolyl]-3- [8-(5-nitro-2 2 alkenyl)]urea

采用实施例 1 的制备方法，将其中的中间体 41 改为中间体 73, 得到标题化合物，为白色固体。 The title compound was obtained as a white solid.

^-NMRCCDC^, 400MHz ) δ: 8.19 (d, 1H, 7=9.2 Hz) , 7.87(s， 1H)， 7.71 (d, 1H， /=9.2 Hz) , 7.19-7.35 (m, 5H)， 6.68 (s, 1H)， 6.35 (s, 1H)， 6.06 (m, 1H)， 4.78 (t, 2H)， 2.35 (s, 3H) , 1.37 (s, 9H)。 ^-NMRCCDC^, 400MHz) δ: 8.19 (d, 1H, 7=9.2 Hz), 7.87(s, 1H), 7.71 (d, 1H, /=9.2 Hz), 7.19-7.35 (m, 5H), 6.68 (s, 1H), 6.35 (s, 1H), 6.06 (m, 1H), 4.78 (t, 2H), 2.35 (s, 3H), 1.37 (s, 9H).

MS (FAB) m/z: 448.2 [M+l〗+。实施例 8: 1- [3-叔丁基 1-苯基 -15~5-吡唑基 ] 3-{8-{3， 4-二氢 - 5- [2- (4-***啉基）乙氧基] - 2^-色烯基 }}脲 MS (FAB) m/z: 448.2 [M+l]+. Example 8: 1-[3-tert-butyl 1-phenyl-15~5-pyrazolyl] 3-{8-{3,4-dihydro-5-[2-(4-morphinolinyl) Ethoxy] - 2^-chromenyl}}urea

在 50mL三口瓶中加入 20mL干燥的二氯甲烷，冷却到 -10"C，加入三光气（109mg， 0.36mmol ) ，慢慢滴加中间体 50 ( 280mg， 1.0麵 ol) 溶于 10mL干燥二氯甲烷的溶液，有白色沉淀产生，反应 1小时，滴加 0.4mL千燥的三乙胺，沉淀溶解。加入中间体 12 ( 129mg, 0.6mmol ) ，升温至室温，反应 5天，倒入 50mL水中，用二氯甲烷提取 3次，有机层用饱和食盐水洗涤，无水疏酸钠千燥，柱分离（洗脱体系：石油醚 /乙酸乙酯）得到标题化合物 136mg，为白色晶体，收率 26.2%。 Add 20 mL of dry dichloromethane to a 50 mL three-necked flask, cool to -10 ° C, add triphosgene (109 mg, 0.36 mmol), and slowly add the intermediate 50 (280 mg, 1.0 Å) to 10 mL of dry dichloro A solution of methane was obtained as a white precipitate. After reacting for 1 hour, 0.4 mL of triethylamine was added dropwise, and the precipitate was dissolved. Intermediate 12 (129 mg, 0.6 mmol) was added, and the mixture was warmed to room temperature, reacted for 5 days, and poured into 50 mL of water. The extract was extracted with EtOAc (3 mL). It was a white crystal with a yield of 26.2%.

^XH- R ( CDCI3, 400MHz ) δ： 7.67(d, 1H， /=8.4 Hz), ^X H- R ( CDCI3, 400MHz ) δ: 7.67(d, 1H, /=8.4 Hz),

7.32-7.45 (m, 2H) , 7.34 (m, 3H), 7.28(m, 1H)， 7.03 (s, 1H)，7.32-7.45 (m, 2H) , 7.34 (m, 3H), 7.28 (m, 1H), 7.03 (s, 1H),

6.35 (s, 1H)， 6.31 (d, 1H， 7=10.8 Hz), 4.04 - 4.06 (m， 4H)， 3.70(t, 4H, 7=4.8 Hz) , 2.77 (t, 2H， 7=5.6 Hz) , 2.56-2.61 (m， 6H)， 1.90 (p, 2H), 1.34 (s, 9H)。 6.35 (s, 1H), 6.31 (d, 1H, 7 = 10.8 Hz), 4.04 - 4.06 (m, 4H), 3.70 (t, 4H, 7 = 4.8 Hz), 2.77 (t, 2H, 7 = 5.6 Hz) ), 2.56-2.61 (m, 6H), 1.90 (p, 2H), 1.34 (s, 9H).

MS (FAB) m/z: 520.2 [M+l]⁺ ₀ 实施例 9: 1- O叔丁基- 1-(4-氟苯基 )-1^"5-吡唑基 ]-3-{8-{3， 4 -二氢 -5- U- (4-***淋基）乙氧基] 2^色烯基 }}脲 MS (FAB) m/z: 520.2 [M+l] ⁺ ₀ Example 9: 1-O-tert-butyl- 1-(4-fluorophenyl)-1^"5-pyrazolyl]-3-{ 8-{3,4-dihydro-5- U-(4-morphine)-ethoxy] 2^-alkenyl}}urea

采用实施例 8的制备方法，将其中的中间体 12改为中间体 14，得到标题化合物，为白色固体。 The title compound was obtained as a white solid.

'H-NMR ( CDCI3, 400MHz ) δ： 7.64 (d, 1H， /=8.8 Hz) , 'H-NMR (CDCI3, 400MHz) δ: 7.64 (d, 1H, /=8.8 Hz),

7.38-7.41 (m, 3H) , 7.32 (s, 1H)， 6.99 (m, 2H) , 6.30-6.32 (m, 2H), 4.04 - 4.08 (m, 4H) , 3.71 (t, 4H, 7=4.8 Hz) , 2.79 (t, 2H， 7=5.6 Hz), 2.56-2.59 (m, 6H)， 1.90 (p, 2H)， 1.32 (s, 9H)。 7.38-7.41 (m, 3H) , 7.32 (s, 1H), 6.99 (m, 2H), 6.30-6.32 (m, 2H), 4.04 - 4.08 (m, 4H) , 3.71 (t, 4H, 7=4.8 Hz), 2.79 (t, 2H, 7=5.6 Hz), 2.56-2.59 (m, 6H), 1.90 (p, 2H), 1.32 (s, 9H).

MS (FAB) m/z: 538.1 [M+l]⁺。实施例 10: 1-[3-叔丁基-1-(4-氯苯基）-1^5-吡唑基] 3-{8 {3， 4 -二氢 -5- U- (4 ***啉基）乙氧基〗 -2^·色烯基 }}脲 MS (FAB) m/z: 538.1 [M+l] ⁺ . Example 10: 1-[3-tert-Butyl-1-(4-chlorophenyl)-1^5-pyrazolyl] 3-{8 {3,4-dihydro-5- U- (4 morphine) Phenyl)ethoxylated -2^·alkenyl}}urea

釆用实施例 8 的制备方法，将其中的中间体 12改为中间体 15，得到标题化合物，为白色固体。 The title compound was obtained as a white solid.

'H-NMRC CDCI3, 400MHz ) δ: 7.63 (d, 1H， /=8.0 Hz)， 7.42 (m， H)， 7.35 (m, 2H) , 7.11 (s, 1H)， 6.55(s， 1H)， 6.37 (s, 1H)， .34 (d, 1H), 4.08 (m, 4H), 3.74 (t, 4H, /=4.4 Hz) , 2.82 (t, H， /=5.6 Hz) , 2.62-2.65 (m, 6H), 1.94 (p, 2H)， 1.36 (s, 9H)。 'H-NMRC CDCI3, 400MHz) δ: 7.63 (d, 1H, /=8.0 Hz), 7.42 (m, H), 7.35 (m, 2H), 7.11 (s, 1H), 6.55(s, 1H), 6.37 (s, 1H), .34 (d, 1H), 4.08 (m, 4H), 3.74 (t, 4H, /=4.4 Hz), 2.82 (t, H, /=5.6 Hz), 2.62-2.65 ( m, 6H), 1.94 (p, 2H), 1.36 (s, 9H).

MS (FAB) m/z: 554.0 [M+l]⁺。实施例 11: l-[3-叔丁基- 1 -（4-溴苯基）-l 5-吡唑基 ]-3 - {⁸-{3, 4 -二氢 -5 -〖2- (4-***啉基）乙氧基] - 2^色烯基 }}脲 MS (FAB) m/z: 554.0 [M+l] ⁺ . Example 11: l-[3-tert-butyl-1 -(4-bromophenyl)-l 5-pyrazolyl]-3 - { ⁸ -{3, 4 -dihydro-5 -〖2- 4-morphocolinyl)ethoxy] - 2^-alkenyl}}urea

采用实施例 8的制备方法，将其中的中间体 12改为中间体 16, 得到标题化合物，为白色固体。 The title compound was obtained as a white solid.

^-NMRC CDC1₃, 400MHz ) δ: 7.64 (d, 1Η, /=8. OHz), 7.47(m, 2H)， 7.37 (m, 2H)， 7.20(s, 1H)， 6.88 (s, 1H)， 6.37 (s, 1H)， 6.34 (d, 1H， 7=8.8 Hz) , 4.08 (m, 4H)， 3.73 (t, 4H， 7=4.4 Hz) , 2.83(t, 2H, 7=5.6 Hz)， 2.60-2.61 (m, 6H) , 1.92 (p, 2H) , 1.36 (s, 9H)。 ^-NMRC CDC1 ₃ , 400MHz ) δ: 7.64 (d, 1Η, /=8. OHz), 7.47(m, 2H), 7.37 (m, 2H), 7.20(s, 1H), 6.88 (s, 1H) , 6.37 (s, 1H), 6.34 (d, 1H, 7=8.8 Hz) , 4.08 (m, 4H), 3.73 (t, 4H, 7=4.4 Hz), 2.83(t, 2H, 7=5.6 Hz) , 2.60-2.61 (m, 6H), 1.92 (p, 2H), 1.36 (s, 9H).

MS (FAB) m/z: 598.0 [M+l]⁺。实施例 12: 1- [3-叔丁基 - 1- (4-甲氧基苯基）

吡唑基]- 3- {8- {3, 4-二氢- 5- [2- (4 -***淋基）乙氧基] - 2^·色烯基 }} 脲 MS (FAB) m/z: 598.0 [M+l] ⁺ . Example 12: 1-[3-tert-butyl-1-(4-methoxyphenyl)

Pyrazolyl]-3-{8- {3, 4-dihydro-5-[2-(4-morphine)ethoxy]-2^·enyl}}urea

采用实施例 8 的制备方法，将其中的中间体 12 改为中间体 13，得到标题化合物，为白色固体。 The title compound was obtained as a white solid.

H-N R( CDC1₃, 400MHz ) δ: 7.70 (d, IH, 7=8.4 Hz)， 7.35 (m, 2H)， 7.24 (s, 1H)， 6.90(m， 2H) , 6.52 (s, IH) , 6.34 (s, IH)， 6.32 (d, 1H)， 4.08 (m, 4H) , 3.79 (s, 3H) , 3.74 (t_} 4H, 7=4.4 Hz), 2.81 (t, 2H， 7=6.0 Hz) , 2.59-2.63 (m, 6H), 1.93 (p, 2H) , 1.35 (s, 9H)。 HN R ( CDC1 ₃ , 400MHz ) δ: 7.70 (d, IH, 7=8.4 Hz), 7.35 (m, 2H), 7.24 (s, 1H), 6.90 (m, 2H), 6.52 (s, IH) , 6.34 (s, IH), 6.32 (d, 1H), 4.08 (m, 4H) , 3.79 (s, 3H) , 3.74 (t _} 4H, 7=4.4 Hz), 2.81 (t, 2H, 7=6.0 Hz ), 2.59-2.63 (m, 6H), 1.93 (p, 2H), 1.35 (s, 9H).

MS (FAB) m/z: 550.1 [M+l]⁺。实施例 13: 1- [3-叔丁基 -1- (4-氨基磺酰基苯基） -I 5-吡唑基]- 3- {8- {3， 4 -二氢 -5- [2 -（4-***淋基）乙氧基] - 2^·色烯基 }} 脲采用实施例 8 的制备方法，将其中的中间体 12 改为中间体 18，得到标题化合物，为白色固体。 MS (FAB) m/z: 550.1 [M+l] ⁺ . Example 13: 1-[3-tert-Butyl-1-(4-aminosulfonylphenyl)-I 5-pyrazolyl]- 3-{8- {3,4-dihydro-5-[2 -(4-morphine)-ethoxy] - 2^·alkenyl}} Urea The title compound was obtained as a white solid.

^XH-NMR( CDC1₃₅400MHz ) δ 8.80 (d, 2Η, 7=8.8 Hz) , 7.78 (d, 2H, /=8.8 Hz) , 7.66 (d, IH), 6.29 (d, IH, 7=9.2 Hz) , 5.56(s， IH), 5.23 (t, 2H)， 4.12 (t, 2H)， 3.79 (m, 6H)， 2.90 (t, 2H) , 2.63-2.70 (m， 6H) , 2.00 (p, 2H)， 1.29 (s, 9H)。 ^X H-NMR ( CDC1 ₃₅ 400MHz ) δ 8.80 (d, 2Η, 7=8.8 Hz), 7.78 (d, 2H, /=8.8 Hz), 7.66 (d, IH), 6.29 (d, IH, 7=9.2 Hz), 5.56(s, IH), 5.23 (t, 2H), 4.12 (t, 2H), 3.79 (m, 6H), 2.90 (t, 2H), 2.63-2.70 (m, 6H), 2.00 (p , 2H), 1.29 (s, 9H).

MS (FAB) m/z: 599,1 [M+l]⁺。实施例 14 : l-[3-叔丁基 - 1-(4-硝基苯基） -1^5-吡唑基]- 3- {8-{3， 4-二氢- 5- [2- (4-***啉基）乙氧基] -2^色烯基 }} 脲 MS (FAB) m/z: 599,1 [M+l] ⁺ . Example 14: l-[3-tert-butyl-1-(4-nitrophenyl)-1^5-pyrazolyl]- 3-{8-{3,4-dihydro- 5- [2 - (4-morphinolinyl)ethoxy] -2^-alkenyl}} Urea

采用实施例 8 的制备方法，将其中的中间体 12 改为中间体 17，得到标题化合物，为黄色固体。 The title compound was obtained as a yellow solid.

'H-NMRC CDC1₃, 400MHz ) δ: 8.13 (d, 2Η， 7=9.6 Hz) , 7.84 (s, 1Η)， 7.73 (d, 2Η， 7=9.2 Hz) , 7.55 (d, IH, 7=8.4 Hz) , 7.43 (s, IH), 6.38 (s, IH), 6.29(d, 1H， 7=8.8 Hz) , 4.07 (m, 4H) , 3.72 (t 4H， 7=4.8 Hz) , 2.81 (t, 2H)， 2.58-2.62 (m, 6H)， 1.91 (p, 2H)，'H-NMRC CDC1 ₃ , 400MHz ) δ: 8.13 (d, 2Η, 7=9.6 Hz), 7.84 (s, 1Η), 7.73 (d, 2Η, 7=9.2 Hz) , 7.55 (d, IH, 7= 8.4 Hz), 7.43 (s, IH), 6.38 (s, IH), 6.29 (d, 1H, 7=8.8 Hz), 4.07 (m, 4H), 3.72 (t 4H, 7=4.8 Hz), 2.81 ( t, 2H), 2.58-2.62 (m, 6H), 1.91 (p, 2H),

I.33 (s, 9H)。 I.33 (s, 9H).

MS (FAB) m/z: 565.0 [M+l]⁺。实施例 15 : 1- [3-叔丁基 - 1-(4-甲基苯基）- 1H-5-吡唑基〗 -3- {8- [3， 4 -二氢 -5- (4-***啉基酰基甲氧基) -²^"色烯基] } 脲 MS (FAB) m/z: 565.0 [M+l] ⁺ . Example 15: 1-[3-tert-butyl-1-(4-methylphenyl)-1H-5-pyrazolyl-3-(8-[8,4-dihydro-5- (4 -morpholinyl acylmethoxy) - ² ^"chromenyl" } urea

采用实施例 8 的制备方法，将其中的中间体 12 改为中间体 Using the preparation method of Example 8, the intermediate 12 was changed to an intermediate.

II, 中间体 50改为中间体 59, 得到标题化合物，为白色固体。 II, Intermediate 50 was changed to intermediate 59 to give the title compound as white solid.

'Ε-ΜΠ CDC1₃, 400MHz ) δ: 7.75 (d, IH, 7=9.2 Hz) , 7.34 (d,'Ε-ΜΠ CDC1 ₃ , 400MHz ) δ: 7.75 (d, IH, 7=9.2 Hz), 7.34 (d,

2H, 7=8.4 Hz) , 7.25 (d, 2H)， 6.38 (s, IH)， 6.34 (d, IH, 7=9.2 Hz), 4.64 (s, 2H), 4.11 (t, 2H, 7=3.6 Hz) , 3.63 - 3,67 (m， 8H),2H, 7=8.4 Hz), 7.25 (d, 2H), 6.38 (s, IH), 6.34 (d, IH, 7=9.2 Hz), 4.64 (s, 2H), 4.11 (t, 2H, 7=3.6 Hz), 3.63 - 3,67 (m, 8H),

2.67 (t, 2H, 7=6.4 Hz), 2.37 (s, 3H) , 1.95 (p, 2H) , 1.36(s, 9H)。 2.67 (t, 2H, 7=6.4 Hz), 2.37 (s, 3H), 1.95 (p, 2H), 1.36(s, 9H).

MS (FAB) m/z: 548.1 [M+l]⁺。实施例 16: l-(3-叔丁基 - 5-异喁唑基） -3-{8-{3, 4-二氢 -5- [2- (4-***啉基）乙氧基] 色烯基 }}脲 MS (FAB) m/z: 548.1 [M+l] ⁺ . Example 16: l-(3-tert-Butyl-5-isoxazolyl)-3-{8-{3,4-dihydro-5-[2-(4-morphinolinyl)ethoxy] Alkenyl}}urea

采用实施例 8 的制备方法，将其中的中间体 12 改为中间体 28, 得到标题化合物，为白色固体。 The title compound was obtained as a white solid.

^XH-NMR( CDC1₃, 400MHz ) 5: 8.59 (s， IH)， 7.67 (d， IH, 7=8.0 Hz), 6.36 (d, IH, /=9.2 Hz) , 6.12 (s, IH)， 4.08-4.10(m, 4H) , ^X H-NMR (CDC1 ₃ , 400MHz ) 5: 8.59 (s, IH), 7.67 (d, IH, 7 = 8.0 Hz), 6.36 (d, IH, /=9.2 Hz), 6.12 (s, IH), 4.08-4.10(m, 4H),

3.75 (t, 4H, /=4.4 Hz) , 2.83(t, 2H， 7=5.6 Hz) , 2.60 - 2.64 (m， 6H)， 1.92 (p, 2H)， 1.30(s, 9H)。 3.75 (t, 4H, /=4.4 Hz), 2.83 (t, 2H, 7 = 5.6 Hz), 2.60 - 2.64 (m, 6H), 1.92 (p, 2H), 1.30 (s, 9H).

MS (FAB) m/z: 445.1 [M+l]+。实施例 17: l-(5-叔丁基 - 3-异喁唑基）- 3-{8-{3, 4-二氢 -⁵-[²-(⁴-***啉基）乙氧基] - 色烯基脲 MS (FAB) m/z: 445.1 [M+l]+. Example 17: l-(5-tert-Butyl-3-isoxazolyl)-3-{8-{3,4-dihydro- ^5- [ ^2- ( ⁴ -morpholino)ethoxy] - color alkenyl urea

采用实施例 8的制备方法，将其中的中间体 12改为 3-氨基 -5 -叔丁基异喁唑，得到标题化合物，为白色固体。 The title compound was obtained as a white solid.

'H-NMRC CDC1_3J 400MHz ) δ: 8.75 (s， 2Η) , 7.86 (d, 1Η， /=8.8 Hz), 6.37 (d, 1H， /=8.8 Hz) , 6.07(s, IH)， 4.23(t, 2H， 7=4.8 Hz), 4.10 (t. 2H)， 3.74 (t, 4H， 7=4.4 Hz) , 2.82 (t, 2H, /=5.2 Hz), 2.61-2.67 (m, 6H) , 1.99 (p, 2H)， 1.34 (s, 9H)。 'H-NMRC CDC1 _3J 400MHz ) δ: 8.75 (s, 2Η), 7.86 (d, 1Η, /=8.8 Hz), 6.37 (d, 1H, /=8.8 Hz), 6.07(s, IH), 4.23( t, 2H, 7=4.8 Hz), 4.10 (t. 2H), 3.74 (t, 4H, 7=4.4 Hz), 2.82 (t, 2H, /=5.2 Hz), 2.61-2.67 (m, 6H), 1.99 (p, 2H), 1.34 (s, 9H).

MS (FAB) m/z: 445.1 [M+l]⁺。实施例 18 : 叔丁基 - 3-(4-甲基苯基）- 吡唑 ] -3- {8- {3, 4-二氢 -5- [2- (4-***啉基）乙氧基] -²^色烯基 }} 脲 MS (FAB) m/z: 445.1 [M+l] ⁺ . Example 18: tert-butyl-3-(4-methylphenyl)-pyrazole]-3-{8-{3,4-dihydro-5-[2-(4-morphinolinyl)ethoxylate Base] - ² ^color alkenyl}} Urea

采用实施例 8 的制备方法，将其中的中间体 12 改为中间体 33, 得到标题化合物，为白色固体。 The title compound was obtained as a white solid.

'H-NMRCCDCls, 400MHz ) δ: 7.70(s, IH)， 7.63 (d, IH, 7=9.2 Hz), 7.14-7.17 (m, 4H) , 6.86 (s, IH)， 6.29 (d, IH, 7=8.4 Hz) , 'H-NMRCCDCls, 400MHz) δ: 7.70(s, IH), 7.63 (d, IH, 7=9.2 Hz), 7.14-7.17 (m, 4H), 6.86 (s, IH), 6.29 (d, IH, 7=8.4 Hz),

5.80 (s, IH), 4.04-4.06 (m, 4H) , 3.71 (t, 4H, 7=4.0 Hz),5.80 (s, IH), 4.04-4.06 (m, 4H), 3.71 (t, 4H, 7=4.0 Hz),

2.78 (t, 2H)， 2.56-2.58 (m, 6H) , 2.36 (s, 3H) , 1.92 (p, 2H)， 1.43 (s, 9H)。 2.78 (t, 2H), 2.56-2.58 (m, 6H), 2.36 (s, 3H), 1.92 (p, 2H), 1.43 (s, 9H).

MS (FAB) m/z: 534.2 [M+l]+。实施例 19 : l-[4-叔丁基 -1- (4-甲基苯基） - 咪唑基] - 3-{8- {3， 4 -二氢 -5- [2- (4-***啉基）乙氧基] -2^·色烯基 }} 脲 MS (FAB) m/z: 534.2 [M+l]+. Example 19: l-[4-tert-Butyl-1-(4-methylphenyl)-imidazolyl]-3-{8-{3,4-dihydro-5-[2-(4-morphine) Phenyl)ethoxy]-2^·enyl}} Urea

采用实施例 8 的制备方法，将其中的中间体 12改为中间体 35，得到标题化合物，为白色固体。 The title compound was obtained as a white solid.

'H-NMR (CDC1₃, 400MHz) δ: 11.56 (s, IH), 7.98 (d, 1H， 7=9.2 Hz), 7.21 - 7.26 (m， 4H) , 6.75 (s, 1H)， 6.45(s, IH)，'H-NMR (CDC1 ₃ , 400MHz) δ: 11.56 (s, IH), 7.98 (d, 1H, 7=9.2 Hz), 7.21 - 7.26 (m, 4H) , 6.75 (s, 1H), 6.45(s , IH),

6.37 (d, 1H， 7=8.8 Hz) , 4.29(t, 2H) , 4.08 (t, 2H， 7=5.6 Hz) ,6.37 (d, 1H, 7=8.8 Hz), 4.29(t, 2H) , 4.08 (t, 2H, 7=5.6 Hz),

3.71(t, 4H， 7=4.8 Hz), 2.79 (t, 2H)， 2.70(t, 2H)， 2.58 (t, 4H, /=4.4 Hz), 2.39 (s, 3H)， 2.32 (p, 2H) , 1.34 (s, 9H)。 3.71(t, 4H, 7=4.8 Hz), 2.79 (t, 2H), 2.70(t, 2H), 2.58 (t, 4H, /=4.4 Hz), 2.39 (s, 3H), 2.32 (p, 2H) ), 1.34 (s, 9H).

MS (FAB) m/z: 534.2 [M+l]+。实施例 20 : l-[3-叔丁基 -l-(4-甲基苯基） -1H-5-吡唑基]- 3-{8-{3, 4-二氢 -5- [2- (4-吡啶基）氧基乙氧基] - 色烯基 "脲 MS (FAB) m/z: 534.2 [M+l]+. Example 20: l-[3-tert-butyl-l-(4-methylphenyl)-1H-5-pyrazolyl]- 3-{8-{3,4-dihydro-5-[2 - (4-pyridyl)oxyethoxy]-chromenyl "urea

采用实施例 15的制备方法，将其中的中间体 59改为中间体 56，得到标题化合物，为白色固体。 'H-NMRC CDCI3, 400MHz ) 5： 8.44 (dd, 2H， 7=4.8 Hz, 1.2Hz)，The title compound was obtained as a white solid. 'H-NMRC CDCI3, 400MHz) 5: 8.44 (dd, 2H, 7=4.8 Hz, 1.2Hz),

7.79(d, 1H， /=8.8 Hz) , 7.33 (d, 2H， /=8.0 Hz)， 7.28(s， IH),7.79 (d, 1H, /=8.8 Hz), 7.33 (d, 2H, /=8.0 Hz), 7.28(s, IH),

7.21(d, 2H)， 6.91 (dd, 2H， /=4.8 Hz, 1.6Hz)， 6.43 (s, IH),7.21(d, 2H), 6.91 (dd, 2H, /=4.8 Hz, 1.6Hz), 6.43 (s, IH),

6.40 (d, 1H， 7=9.2 Hz) , 6.37 (s, IH), 4.40(t, 2H， 7=5.2 Hz) ,6.40 (d, 1H, 7=9.2 Hz), 6.37 (s, IH), 4.40(t, 2H, 7=5.2 Hz),

4.33 (t, 2H， 7=5.2 Hz), 4.12 (t, 2H) , 2.58 (t, 2H, 7=6.8 Hz) , 2.36 (s， 3H)， 1.90 (p, 2H)， 1.36 (s, 9H)。 4.33 (t, 2H, 7=5.2 Hz), 4.12 (t, 2H), 2.58 (t, 2H, 7=6.8 Hz), 2.36 (s, 3H), 1.90 (p, 2H), 1.36 (s, 9H) ).

MS (FAB) m/z: 542.0 [M+l]⁺ ₀ 、实施例 21 : l-[3-叔丁基 - 1-(4-甲基苯基）- 1H-5-吡唑基〗- 3-{8-{3, 4-二氢- 5 - {2- [4- (顺式 -2， 6 -二甲基）***啉基] 乙氧基 } -2^色烯基 }}脲 MS (FAB) m / z: 542.0 [M + l] + 0, Example 21: l- [3- tert-butyl - 1 - (4-methylphenyl) - 1H-5- pyrazolyl〗 - 3-{8-{3,4-dihydro-5-{2-[4-(cis-2,6-dimethyl)morphinolinyl]ethoxy}-2^-alkenyl}}urea

采用实施例 15的制备方法，将其中的中间体 59改为中间体 55, 得到标题化合物，为白色固体。 The title compound was obtained as a white solid.

'H-NMRC CDCI3, 400MHz ) δ: 7.71 (d, IH, /=9.2 Hz) , 7.31 (d, 2H, /=8.4 Hz) , 7.21 (d, 2H) , 7.17(s， IH)， 6.31-6.36 (m, 3H) , 4.08-4.10 (m, 4H)， 3.71 (m, 2H)， 2.80-2.86 (m, 4H) , 2.63 (t, 2H, 7=6.4 Hz) , 2.36 (s, 3H) , 1.92-1.95 (m, 4H) , 1.35 (s, 9H) , 1.17 (d, 3H)， 1.15 (d, 3H)。 'H-NMRC CDCI3, 400MHz) δ: 7.71 (d, IH, /=9.2 Hz), 7.31 (d, 2H, /=8.4 Hz), 7.21 (d, 2H), 7.17(s, IH), 6.31- 6.36 (m, 3H) , 4.08-4.10 (m, 4H), 3.71 (m, 2H), 2.80-2.86 (m, 4H), 2.63 (t, 2H, 7=6.4 Hz), 2.36 (s, 3H) , 1.92-1.95 (m, 4H), 1.35 (s, 9H), 1.17 (d, 3H), 1.15 (d, 3H).

MS (FAB) m/z: 562.2 [M+l]⁺。实施例 22 : l-[3-叔丁基 -1- (4-甲基苯基） -1H-5-吡唑基] -3-{8 - {3, 4 -二氢 -5- [2- (1-咪唑基）乙氧基] 色烯基 }} 脲 MS (FAB) m/z: 562.2 [M+l] ⁺ . Example 22: l-[3-tert-Butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{8 - {3,4-dihydro-5-[2 - (1-imidazolyl)ethoxy]chromenyl}} Urea

采用实施例 15的制备方法，将其中的中间体 59改为中间体 52, 得到标题化合物，为白色固体。 The title compound was obtained as a white solid.

Hz) , 7.73(s， IH), 7.53 (s, 1H)， 7.32 (d, 2H， 7=8.0 Hz), 7.15 (d, 2H, 7=8.0 Hz), 6.93 (s, 1H)， 6.89(s， 1H)， 6.41 (s, 1H)， 6.22 (d, 1H, 7=8.8 Hz), 4.32 (t, 2H， /=4.8 Hz), 4.12(t, 2H， /=5.6 Hz),

Hz) , 7.73(s, IH), 7.53 (s, 1H), 7.32 (d, 2H, 7=8.0 Hz), 7.15 (d, 2H, 7=8.0 Hz), 6.93 (s, 1H), 6.89(s, 1H), 6.41 (s, 1H), 6.22 (d, 1H, 7=8.8 Hz), 4.32 (t, 2H, /=4.8 Hz), 4.12 ( t, 2H, /=5.6 Hz),

3.62 (t, 2H), 2.35 (t, 2H) , 2.32 (s， 3H) , 1.61 (p, 2H) , 1.35 (s, 9H)。 3.62 (t, 2H), 2.35 (t, 2H), 2.32 (s, 3H), 1.61 (p, 2H), 1.35 (s, 9H).

MS (FAB) m/z: 515.2 [M+l]⁺„ 实施例 23 : l-[3-叔丁基 -l-(4-甲基苯基） -1H- 5-吡唑基]- 3-{8-{3, 4-二氢- 5 - [2 -（1-1， 2, 4 -三氮唑基）乙氧基] -2 - 色烯基 }}脲 MS (FAB) m/z: 515.2 [M+l] ^{+ <} /RTI></RTI> Example 23: l-[3-tert-butyl-l-(4-methylphenyl)-1H 5-pyrazolyl]- 3 -{8-{3,4-Dihydro-5-[2-(1-1, 2,4-triazolyl)ethoxy]-2-isosyl}}urea

采用实施例 15的制备方法，将其中的中间体 59改为中间体 53, 得到标题化合物，为白色固体。 The title compound was obtained as a white solid.

^XH-NMR(CDC1₃, 400MHz ) δ: 8.08 (s 1H) , 7.82 - 7.84 (m, 2H)， 7.45(s， 1H)， 7.32 (d, 2H， 7=8.4 Hz) , 7.17 (d, 2H, 7=8.4 Hz) , 6.40 (s, IH), 6.27 (d, 1H， /=9.2 Hz) , 4.56 (t, 2H, /=4.8 Hz) , ^X H-NMR (CDC1 ₃ , 400 MHz ) δ: 8.08 (s 1H) , 7.82 - 7.84 (m, 2H), 7.45 (s, 1H), 7.32 (d, 2H, 7 = 8.4 Hz), 7.17 (d, 2H, 7=8.4 Hz), 6.40 (s, IH), 6.27 (d, 1H, /=9.2 Hz), 4.56 (t, 2H, /=4.8 Hz),

4.23 (t, 2H, 7=4.8 Hz), 3.77 (t, 2H) , 2.33-2.36 (m, 5H)， 1.69 (p, 2H), 1.35 (s, 9H)。 4.23 (t, 2H, 7=4.8 Hz), 3.77 (t, 2H), 2.33-2.36 (m, 5H), 1.69 (p, 2H), 1.35 (s, 9H).

MS (FAB) m/z: 516.3 [M+l]+。实施例 24: 1-[3-叔丁基-1-（4-氯苯基)-1^-5-吡唑基]-3-{8-{3， 4-二氢- 5- {2- [4- (顺式 -2， 6-二甲基） ***啉基]乙氧基 } -1B- 色烯基 }}脲 MS (FAB) m/z: 516.3 [M+l]+. Example 24: 1-[3-tert-Butyl-1-(4-chlorophenyl)-1^-5-pyrazolyl]-3-{8-{3,4-dihydro- 5- {2 - [4-(cis-2,6-dimethyl)morphinolinyl]ethoxy} -1B-chromenyl}}urea

釆用实施例 8 的制备方法，将其中的中间体 12 改为中间体 5，中间体 50改为中间体 55，得到标题化合物，为白色固体。 - NMR(CDC1₃, 400MHz) δ: 7.63 (d, 1H， 7=8.4 Hz) , 7.42 (d, H， /=8.4 Hz) , 7.34 (d, 2H, 7=8.8 Hz), 7.16 (s, 1H)， 6.96 (s, H)， 6.37 (s, 1H)， 6.34 (d, IH, /=8.8 Hz) , 4.06-4.09 (m, 4H)， .70 (m, 2H)， 2.80—2.85 (m， 4H) , 2.63(t, 2H， 7=6.4 Hz), 1.91-1.95 (m, 4H)， 1.34(s, 9H) , 1.17(d, 3H)， 1.15 (d, 3H)。 The title compound was obtained as a white solid. - NMR (CDC1 ₃ , 400MHz) δ: 7.63 (d, 1H, 7=8.4 Hz), 7.42 (d, H, /=8.4 Hz), 7.34 (d, 2H, 7=8.8 Hz), 7.16 (s, 1H), 6.96 (s, H), 6.37 (s, 1H), 6.34 (d, IH, /=8.8 Hz), 4.06-4.09 (m, 4H), .70 (m, 2H), 2.80-2.85 ( m, 4H) , 2.63(t, 2H, 7=6.4 Hz), 1.91-1.95 (m, 4H), 1.34(s, 9H), 1.17(d, 3H), 1.15 (d, 3H).

MS (FAB) m/z: 582.1 [M+l]⁺。实施例 25: 1- [3 叔丁基 -1- (3， 4-二甲基苯基）- 1^"5-吡唑基] -3-{8-{3， 4 -二氢 -5- [2- (4-***啉基）乙氧基] -2 色烯基 }} 脲 MS (FAB) m/z: 582.1 [M+l] ⁺ . Example 25: 1-[3 tert-Butyl-1-(3,4-dimethylphenyl)-1^"5-pyrazolyl]-3-{8-{3,4-dihydro-5 - [2- (4-morphinolinyl)ethoxy] -2 alkenyl}} Urea

采用实施例 8 的制备方法，将其中的中间体 12改为中间体 Using the preparation method of Example 8, the intermediate 12 was changed to an intermediate.

19, 得到标题化合物，为白色固体。 19, the title compound was obtained as a white solid.

'H-NMRC CDC1₃, 400MHz ) δ: 7.68 (d, 1H， 7=8.8 Hz) , 7.30 (s, 1H)， 7.19 (s, IH), 7.08-7.10 (m, 2H)， 6.80 (s, IH)， 6.34 (s, IH), 6.32 (d, IH, =8.8 Hz) , 4.04-4.06 (m, 4H)， 3.71 (t, 4H, /=4.4 Hz) , 2.79 (t, 2H), 2..57-2.61 (m, 6H), 2.20-2.21 (m, 6H) 1.90 (p, 2H)， 1.34 (s, 9H)。 'H-NMRC CDC1 ₃ , 400MHz ) δ: 7.68 (d, 1H, 7=8.8 Hz), 7.30 (s, 1H), 7.19 (s, IH), 7.08-7.10 (m, 2H), 6.80 (s, IH), 6.34 (s, IH), 6.32 (d, IH, =8.8 Hz), 4.04-4.06 (m, 4H), 3.71 (t, 4H, /=4.4 Hz), 2.79 (t, 2H), 2 ..57-2.61 (m, 6H), 2.20-2.21 (m, 6H) 1.90 (p, 2H), 1.34 (s, 9H).

MS (FAB) m/z: 548.1 [M+l]⁺ ₀ 实施例 26: 1- [3-叔丁基 -1 (3, 4-二氯苯基）- 1^-5-吡唑基] -3 {8- {3, 4-二氢 -5- [2- (4 -***啉基）乙氧基] -2^·色烯基 }} 脲 MS (FAB) m/z: 548.1 [M+l] ⁺ ₀ Example 26: 1-[3-tert-butyl-1 (3, 4-dichlorophenyl)-1^-5-pyrazolyl] -3 {8- {3, 4-Dihydro-5-[2-(4- morphinyl)ethoxy]-2^·chromenyl}} Urea

釆用实施例 8 的制备方法，将其中的中间体 12改为中间体 Using the preparation method of Example 8, the intermediate 12 was changed to an intermediate.

20, 得到标题化合物，为白色固体。 20, the title compound was obtained as a white solid.

^-NMRCCDCL, 400MHz ) δ: 7.76 (d, 1H， /=2.0 Hz) , 7.58 (d, IH), 7.43(d, 1H， 7=8.4 Hz) , 7.37 (d, 1H)， 7.17 (s, 1H)， 6.81 (s IH), 6.37 (s, 1H)， 6.34 (d, IH, 7=8.8 Hz) , 4.09-4.11 (m, 4H) , 3.74 (t, 4H, /-4.4 Hz), 2.83 (t, 2H, 7=5.2 Hz), 2.61 - 2.64 (m， 6H)， 1.94 (p, 2H)， 1.34 (s, 9H)。 ^-NMRCCDCL, 400MHz) δ: 7.76 (d, 1H, /=2.0 Hz), 7.58 (d, IH), 7.43 (d, 1H, 7=8.4 Hz), 7.37 (d, 1H), 7.17 (s, 1H), 6.81 (s IH), 6.37 (s, 1H), 6.34 (d, IH, 7=8.8 Hz), 4.09-4.11 (m, 4H), 3.74 (t, 4H, /-4.4 Hz), 2.83 (t, 2H, 7=5.2 Hz), 2.61 - 2.64 (m, 6H), 1.94 (p, 2H), 1.34 (s, 9H).

MS (FAB) m/z: 588.0 [M+l]⁺。实施例 27 : 1 - [3 -叔丁基 -1 -（3 -甲基苯基） -1^~5-吡唑基] -3- {8- {3， 4-二氢- 5- [2- (4-***淋基）乙氧基] - ²^色烯基 }} 脲 MS (FAB) m/z: 588.0 [M+l] ⁺ . Example 27: 1 - [3 - tert-butyl-1 -(3-methylphenyl)-1^~5-pyrazolyl]-3-{8- {3,4-dihydro-5- [ 2-(4-morphine)-ethoxy] ^-2 ^-alkenyl}}urea

21, 得到标题化合物，为白色固体。21, the title compound was obtained as a white solid.

-醒（ CDCl" 400MHz ) δ： 7.68 (d, 1H, /=8.4 Hz), 7.21-7.26 (m， 4H)， 7.11 (d, IH), 6.83(s, IH), 6.36 (s, 1H)， 6.32 (d, IH, /=8.8 Hz) , 4.05-4.08 (m, 4H) , 3.73 (t, 4H， 7=4.4 Hz), 2.80 (t, 2H， /=5.6 Hz), 2..57-2.62 (m, 6H)， 2.32 (s, 3H), 1.91 (p, 2H) , 1.35 (s, 9H)。 - wake up (CDCl" 400MHz) δ: 7.68 (d, 1H, /=8.4 Hz), 7.21-7.26 (m, 4H), 7.11 (d, IH), 6.83(s, IH), 6.36 (s, 1H) , 6.32 (d, IH, /=8.8 Hz), 4.05-4.08 (m, 4H), 3.73 (t, 4H, 7=4.4 Hz), 2.80 (t, 2H, /=5.6 Hz), 2..57 -2.62 (m, 6H), 2.32 (s, 3H), 1.91 (p, 2H), 1.35 (s, 9H).

MS (FAB) m/z: 534.2 [M+l]⁺ ₀ 实施例 28: 1-[(3-叔丁基-1-萘基）-1^5-吡唑基]-3-{8-{3, 4- 二氢 -5- [2- (4-***啉基）乙氧基] -2^色烯基 }}脲 MS (FAB) m/z: 534.2 [M+l] ⁺ ₀ Example 28: 1-[(3-tert-butyl-1-naphthalenyl)-1^5-pyrazolyl]-3-{8- {3, 4-Dihydro-5-[2-(4-morphinolinyl)ethoxy]-2^isoalkenyl}}urea

22, 得到标题化合物，为白色固体。 22, the title compound was obtained as a white solid.

'H-NMRCCDCla, 400MHz ) δ: 7.85-7.89 (m, 2H) , 7.43-7.45 (m 4H), 7.37 (d, IH), 7.04 (s, IH), 6.46 (m， 2H) , 6.19 (d, 1H， 7=8.8 Hz), 4.03 (t, 2H， 7=5.6 Hz), 3.97 (t, 2H， 7=4.8 Hz) , 3.70(t, 4H, 7=4.4 Hz) , 2.80 (t, 2H， 7=5.2 Hz) , 2.55— 2.57 (m， 6H), 1.85 (p, 2H), 1.38 (s, 9H)。 'H-NMRCCDCla, 400MHz) δ: 7.85-7.89 (m, 2H), 7.43-7.45 (m 4H), 7.37 (d, IH), 7.04 (s, IH), 6.46 (m, 2H) , 6.19 (d , 1H, 7=8.8 Hz), 4.03 (t, 2H, 7=5.6 Hz), 3.97 (t, 2H, 7=4.8 Hz), 3.70(t, 4H, 7=4.4 Hz), 2.80 (t, 2H , 7=5.2 Hz) , 2.55— 2.57 (m, 6H), 1.85 (p, 2H), 1.38 (s, 9H).

MS (FAB) m/z: 570.1 [M+l〗⁺。实施例 29 : l-[3-叔丁基 - 1-(4-甲基苯基）- 1H-5-吡唑基]- 3- {8-{3, 4-二氢 -5- [2 -（1-吡唑基）乙氧基] -2 色烯基 }} 脲 MS (FAB) m/z: 570.1 [M+l] ⁺ . Example 29: l-[3-tert-butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2 -(1-pyrazolyl)ethoxy]-2 alkenyl}} Urea

采用实施例 15的制备方法，将其中的中间体 59改为中间体 54, 得到标题化合物，为白色固体。 Using the preparation method of Example 15, the intermediate 59 was changed to an intermediate. 54 The title compound was obtained as a white solid.

^- MR (CDCI3, 400MHz ) δ: 7.71 (d, 1H) , 7.50-7.53 (m, 2H)， 7.31 (d, 2H)， 7.21(d, 2H, /二 8.0 Hz)， 6.37 (s, 1H)， 6.30 (d, 1H， 7=8.4 Hz), 6.26 (t, 1H)， 4.52 (t, 2H， 7=5.2 Hz) , 4.28 (t, 2H, 7=5.2 Hz), 4.07 (t, 2H， 7=5.6 Hz), 2.54 (t, 2H, /=6.4 Hz) , 2.35 (s, 3H), 1.91 (p, 2H), 1.36 (s, 9H)。 ^- MR (CDCI3, 400MHz) δ: 7.71 (d, 1H) , 7.50-7.53 (m, 2H), 7.31 (d, 2H), 7.21 (d, 2H, / 2 8.0 Hz), 6.37 (s, 1H ), 6.30 (d, 1H, 7=8.4 Hz), 6.26 (t, 1H), 4.52 (t, 2H, 7=5.2 Hz), 4.28 (t, 2H, 7=5.2 Hz), 4.07 (t, 2H) , 7=5.6 Hz), 2.54 (t, 2H, /=6.4 Hz), 2.35 (s, 3H), 1.91 (p, 2H), 1.36 (s, 9H).

MS (FAB) m/z: 515.1 [M+l]⁺。实施例 30 : l-[3-叔丁基 -l-(4-甲基苯基）- lfi-5-吡唑基]- 3- {8-{3, 4 -二氢 -5- [2- (1-哌啶 -4-酮基）乙氧基] -²^色烯基 "脲 MS (FAB) m/z: 515.1 [M+l] ⁺ . Example 30: l-[3-tert-Butyl-l-(4-methylphenyl)-lfi-5-pyrazolyl]- 3-{8-{3,4-dihydro-5-[2 - (1-piperidin-4-one)ethoxy] ^-2 ^-alkenyl "urea

采用实施例 15的制备方法，将其中的中间体 59改为中间体 51, 得到标题化合物，为白色固体。 The title compound was obtained as a white solid.

^- MR ( CDCla, 00MHz ) δ： 7.73 (d, 1H， 7=8.8 Hz), 7.30-7.32 (m, 3H), 7.16 (d, 2H)， 6.85 (s, 1H)， 6.34 - 6· 35 (m， 2H)， 4.10(t, 2H), 4.06 (t, 2H) , 2.91 - 2.94 (m， 6H) , 2.62 (t, 2H)， 2.47 (t, 4H， 7=6.0 Hz), 2.32 (s, 3H) , 1.91 (p, 2H) , 1.35 (s 9H)。 ^- MR ( CDCla, 00MHz ) δ: 7.73 (d, 1H, 7=8.8 Hz), 7.30-7.32 (m, 3H), 7.16 (d, 2H), 6.85 (s, 1H), 6.34 - 6· 35 (m, 2H), 4.10(t, 2H), 4.06 (t, 2H), 2.91 - 2.94 (m, 6H), 2.62 (t, 2H), 2.47 (t, 4H, 7=6.0 Hz), 2.32 ( s, 3H), 1.91 (p, 2H), 1.35 (s 9H).

MS (FAB) m/z: 546.0 [M+l]+。实施例 31 : 1 - [3-叔丁基 -l-(4-甲基苯基） -1H-5-吡唑基〗 - 3-{8 - {3, 4 -二氢 -5-[2- (4-***啉基）乙酰胺基] -2 ^色烯基 "脲 MS (FAB) m/z: 546.0 [M+l]+. Example 31: 1 - [3-tert-butyl-l-(4-methylphenyl)-1H-5-pyrazolyl]-3-{8 - {3,4-dihydro-5-[2 - (4-morphinolinyl)acetamido] -2^chromenyl"urea

釆用实施例 15的制备方法，将其中的中间体 59改为中间体 81，得到标题化合物，为白色固体。 The title compound was obtained as a white solid.

-腿 ( CDC1" 400MHz ) δ: 7.94 (d, 1H, 7=8.8 Hz)， 7.47 (s， 1H)， 7.35 (d, 2H， 7=8.4 Hz), 7.23 (d, 2H, /=8.0 Hz)， 6.36 - 6.38 (m, 2H)， 4.12(t， 2H， /=4.4 Hz), 3.79(t, 3.18 (t, 2H)， 2.61-2.68 (m, 6H) , 2.37 (s, 3H)， 2.03 (p - Leg (CDC1" 400MHz) δ: 7.94 (d, 1H, 7=8.8 Hz), 7.47 (s, 1H), 7.35 (d, 2H, 7=8.4 Hz), 7.23 (d, 2H, /=8.0 Hz ), 6.36 - 6.38 (m, 2H), 4.12(t, 2H, /=4.4 Hz), 3.79(t, 3.18 (t, 2H), 2.61-2.68 (m, 6H), 2.37 (s, 3H), 2.03 ( p

1.36 (s, 9H)。 1.36 (s, 9H).

MS (FAB) m/z: 547.2 [M+l]⁺ _e 实施例 32: l-[3-叔丁基 - 1- (4-三氟甲基苯基）- 1 5-吡唑基〗- 3-{8-{3， 4 -二氢 -5 - [2 - (4-***啉基）乙氧基] 色烯基 }} 脲 MS (FAB) m/z: 547.2 [M+l] ⁺ _e Example 32: l-[3-tert-butyl-1-(4-trifluoromethylphenyl)-1 5-pyrazolyl- 3-{8-{3,4-dihydro-5-[2-(4-morphinolinyl)ethoxy]-alkenyl}}urea

采用实施例 8 的制备方法，将其中的中间体 12 改为中间体 26，得到标题化合物，为白色固体。 The title compound was obtained as a white solid.

'H-NMR (CDCls, 400MHz ) d: 7.61-7.65 (m, 5H) , 7.07 (s, 1H)， 6.60(s, 1H)， 6.41(s, 1H) , 6.34 (d, 1H, 7=8.8 Hz), 4.07-4.09 (m, 4H) , 3.74 (t, 4H, 7=4.4 Hz)， 2.82 (t, 2H)， 2.61-2.64 (m, 6H) , 1.92 (p, 2H)， 1.35 (s, 9H)。 'H-NMR (CDCls, 400MHz) d: 7.61-7.65 (m, 5H), 7.07 (s, 1H), 6.60(s, 1H), 6.41(s, 1H), 6.34 (d, 1H, 7=8.8 Hz), 4.07-4.09 (m, 4H), 3.74 (t, 4H, 7=4.4 Hz), 2.82 (t, 2H), 2.61-2.64 (m, 6H), 1.92 (p, 2H), 1.35 (s , 9H).

MS (FAB) m/z: 588.0 [M+l]+。实施例 33 : l-[3-叔丁基 - 1-(4-乙基苯基） -1^5-吡唑基] -³-{8-{3, 4-二氢 5- [2-（4-***啉基）乙氧基] - ²^色烯基 }} 脲 MS (FAB) m/z: 588.0 [M+l]+. Example 33: l- [3- tert-butyl - 1- (4-ethylphenyl) -1 ^ 5-pyrazolyl] - ³ - {8- {3,4-dihydro-5- [2- (4-morphinolinyl)ethoxy] - ² ^chromenyl}} Urea

采用实施例 8 的制备方法，将其中的中间体 12 改为中间体 24, 得到标题化合物，为白色固体。 The title compound was obtained as a white solid.

^-NMRC CDCls, 400MHz ) δ: 7.70 (d, 1Η, 7=8.8 Hz) , 7.32 (d, 2H, 7=8.4 Hz) , 7.16 (d, 2H， =8.0 Hz), 6.93 (s, 1H), 6.34 (s, 1H)， 6.32 (d, 1H， 7=8.8 Hz) , 4.04-4.06 (m, 4H) , 3.70 (t, 4H, 7=4.8 Hz), 2.78 (t, 2H) , 2.57-2.61 (m, 8H)， 1.90 (p, 2H) , 1.34 (s, 9H)， 1.18 (t, 3H, /=7.6 Hz)。 ^-NMRC CDCls, 400MHz) δ: 7.70 (d, 1Η, 7=8.8 Hz), 7.32 (d, 2H, 7=8.4 Hz), 7.16 (d, 2H, =8.0 Hz), 6.93 (s, 1H) , 6.34 (s, 1H), 6.32 (d, 1H, 7=8.8 Hz), 4.04-4.06 (m, 4H), 3.70 (t, 4H, 7=4.8 Hz), 2.78 (t, 2H), 2.57- 2.61 (m, 8H), 1.90 (p, 2H), 1.34 (s, 9H), 1.18 (t, 3H, /=7.6 Hz).

MS (FAB) m/z: 548.1 [M+l]⁺。实施例 34: 1- [3-叔丁基 - 1- (4-叔丁基苯基） -1^5-吡唑基〗 -3- {8-{3， 4-二氢 -5- [2- (4-***啉基）乙氧基] -2^色烯基 }} 脲 MS (FAB) m/z: 548.1 [M+l] ⁺ . Example 34: 1-[3-tert-butyl-1-(4-tert-butylphenyl)-1^5-pyrazolyl-3-(8-{3,4-dihydro-5-[ 2-(4-morphinolinyl)ethoxy]-2^enyl}} Urea

25, 得到标题化合物，为白色固体。 25, the title compound was obtained as a white solid.

'Ε-ΜΠ CDC1₃, 400MHz ) δ: 7.72 (d, IH, 7=8.8 Hz) , 7.34 (d, 2H), 7.26 (m, 2H), 7.18 (s, IH) , 6.34-6.37 (m, 3H) , 4.08 - 4.11 (m， 4H)， 3.74 (t, 4H, 7=4.4 Hz)， 2.82 (t, 2H)，'Ε-ΜΠ CDC1 ₃ , 400MHz ) δ: 7.72 (d, IH, 7=8.8 Hz), 7.34 (d, 2H), 7.26 (m, 2H), 7.18 (s, IH), 6.34-6.37 (m, 3H) , 4.08 - 4.11 (m, 4H), 3.74 (t, 4H, 7=4.4 Hz), 2.82 (t, 2H),

2.62-2.65 (m, 6H) , 1.94 (p, 2H)， 1.35 (s, 9H) , 1.24 (d, 3H) , 1.23 (d, 3H)。 2.62-2.65 (m, 6H), 1.94 (p, 2H), 1.35 (s, 9H), 1.24 (d, 3H), 1.23 (d, 3H).

MS (FAB) m/z: 562.1 [M+l]⁺ ₀ 实施例 35: 1- [3-叔丁基 -l-(4-三氟甲基苯基）-l 5-吡唑基 ]-3-{8-{3, 4 -二氢 -5- [2- (1 -咪唑基）乙氧基] - 色烯基脲 MS (FAB) m/z: 562.1 [M+l] & ^lt _; "&&&&&&&&&&&&&&&& 3-{8-{3,4-dihydro-5-[2-(1-imidazolyl)ethoxy]-chromenylurea

26, 中间体 50改为中间体 52, 得到标题化合物，为白色固体。 The title compound was obtained as a white solid.

^-NMR (CDC1₃, 400MHz ) δ: 8.08 (s, IH) , 7.91 (d, IH,^-NMR (CDC1 ₃ , 400MHz ) δ: 8.08 (s, IH) , 7.91 (d, IH,

7=9.2 Hz), 7.63 (d, 2H， 7=8.4 Hz), 7.54 (d, 2H， 7=8.4 Hz), 7.46 (s, IH), 6.86 (s, IH), 6.74 (s, IH), 6.51 (s， IH), 6.18 (d, IH, 7=8.8 Hz) , 4.29 (t, 2H, 7=4.4 Hz) , 4.06 (t, 2H， /=4.8 Hz) ,7=9.2 Hz), 7.63 (d, 2H, 7=8.4 Hz), 7.54 (d, 2H, 7=8.4 Hz), 7.46 (s, IH), 6.86 (s, IH), 6.74 (s, IH) , 6.51 (s, IH), 6.18 (d, IH, 7=8.8 Hz), 4.29 (t, 2H, 7=4.4 Hz), 4.06 (t, 2H, /=4.8 Hz),

3.23 (t, 2H)， 2.18 (t, 2H， 7=6.4 Hz), 1.34 (s, 9H)。 3.23 (t, 2H), 2.18 (t, 2H, 7=6.4 Hz), 1.34 (s, 9H).

MS (FAB) m/z: 569.3 [M+l]⁺ ₀ 实施例 36： 1- [3-叔丁基 -1- (4-甲基苯基） - 1H 5-吡唑 ]- ³ - {⁸-{⁵-[²- (4-***啉基）乙氧基] -²^色烯基 }}脲在 50mL三口瓶中加入 20mL干燥的二氯甲烷，冷却到 -10Ό，加入三光气（109mg， 0.36mmol ) , 慢慢滴加中间体 65 ( 277mg，MS (FAB) m/z: 569.3 [M+l] ⁺ ₀ Example 36: 1-[3-tert-butyl-1-(4-methylphenyl)-1H 5-pyrazole]- ³ - ^8- { ^5- [ ^2- (4-morphinolinyl)ethoxy] ^-2 ^-alkenyl}}urea Add 20 mL of dry dichloromethane to a 50 mL three-necked flask, cool to -10 Torr, add triphosgene (109 mg, 0.36 mmol), and slowly add the intermediate 65 (277 mg,

1.0讓 ol )溶于 10mL干燥二氯甲烷的溶液，有白色沉淀产生，反应 1小时，滴加 0.4mL干燥的三乙胺，沉淀溶解。加入中间体 111.0 Let ol) dissolve in 10 mL of dry dichloromethane solution, a white precipitate was formed, and reacted for 1 hour, 0.4 mL of dry triethylamine was added dropwise, and the precipitate was dissolved. Adding intermediates 11

( 138mg, 0.6mmol ) ，升温至室温，反应 5天，倒入 50mL水中，用二氯甲烷提取 3次，有机层用饱和食盐水洗涤，无水硫酸钠干燥，柱分离（洗脱体系：石油醚 /乙酸乙酯 =1: 1 )得到标题化合物 145fflg, 为白色晶体，收率 27.3%。 (138mg, 0.6mmol), warmed to room temperature, reacted for 5 days, poured into 50mL of water, extracted with dichloromethane three times, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, column separation (elution system: oil Ether/ethyl acetate = 1 : 1 ) to give the title compound 145ff, as white crystals.

^XH-NMR( CDC1₃, 400MHz ) δ: 7.74 (d, 1H, 7=8.8 Hz) , 7.33 (d, 2H， 7=8.4 Hz), 7.21 (d, 2H, /=8.0 Hz)， 7.13(s， 1H) , 6.72-6.74 (dd, 1H， 7=8.4 Hz, 1.6 Hz), 6.39 (d, 1H， 7=9.2 Hz) , 6.35 (s, 1H)， 6.34 (s, 1H)， 5.72 (m, 1H)， 4.71 (t, 2H， 7=2.0 Hz), 4.11 (t, 2H), 3.74(t, 4H) , 2.82 (t, 2H) , 2.60(t, 4H) , ^X H-NMR ( CDC1 ₃ , 400 MHz ) δ: 7.74 (d, 1H, 7 = 8.8 Hz), 7.33 (d, 2H, 7 = 8.4 Hz), 7.21 (d, 2H, /=8.0 Hz), 7.13 ( s, 1H), 6.72-6.74 (dd, 1H, 7=8.4 Hz, 1.6 Hz), 6.39 (d, 1H, 7=9.2 Hz), 6.35 (s, 1H), 6.34 (s, 1H), 5.72 ( m, 1H), 4.71 (t, 2H, 7=2.0 Hz), 4.11 (t, 2H), 3.74(t, 4H), 2.82 (t, 2H), 2.60(t, 4H) ,

2.36 (s, 3H)， 1.35 (s， 9H)。 2.36 (s, 3H), 1.35 (s, 9H).

MS (FAB) m/z: 532.2 [M+l]+。实施例 37 : l-[3-叔丁基 -l-(4-甲基苯基）- 1H-5-吡唑基]- 3-{8-{3， 4-二氢 -5- [2- (4-吡啶基）乙氧基] -2^·色烯基 }} 脲 MS (FAB) m/z: 532.2 [M+l]+. Example 37: l-[3-tert-butyl-l-(4-methylphenyl)-1H-5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2 - (4-pyridyl)ethoxy] -2^·chromenyl}} Urea

采用实施例 8 的制备方法，将其中的中间体 12 改为中间体 11，中间体 50改为中间体 58, 得到标题化合物，为白色固体。 The title compound was obtained as a white solid.

'H- MR CDC^, 400MHz ) δ: 8.57 (d, 2H, /=4.8 Hz) , 7.75 (d, 1H， 7=9.2 Hz) , 7.38 (s, 1H)， 7.28-7.32 (m, 4H)， 7.12 (d, 2H) , 6.82 (s, 1H)， 6.34 (s, 1H)， 6.27(d, 1H, J=9.2 Hz), 4.14 (t, 2H， 7=6.0 Hz) , 3.94 (t, 2H) , 3.10(t, 2H， 7=6.0 Hz) , 2.47 (t, 2H, 7=6.4 Hz) , 2.28(s, 3H)， 1.82 (p, 2H) , 1.34 (s, 9H)。 'H- MR CDC^, 400MHz ) δ: 8.57 (d, 2H, /=4.8 Hz), 7.75 (d, 1H, 7=9.2 Hz), 7.38 (s, 1H), 7.28-7.32 (m, 4H) , 7.12 (d, 2H), 6.82 (s, 1H), 6.34 (s, 1H), 6.27 (d, 1H, J = 9.2 Hz), 4.14 (t, 2H, 7 = 6.0 Hz), 3.94 (t, 2H), 3.10(t, 2H, 7=6.0 Hz), 2.47 (t, 2H, 7=6.4 Hz), 2.28(s, 3H), 1.82 (p, 2H), 1.34 (s, 9H).

MS (FAB) m/z: 526.2 [M+l]+。实施例 38 : l-[3-叔丁基 - 1-(4-腈基苯基） -1^5-吡唑基]-3-{8-{3， 4 二氢- 5- [2 - (4-***啉基）乙氧基] -²^色烯基 }} 脲 MS (FAB) m/z: 526.2 [M+l]+. Example 38: l-[3-tert-butyl-1-(4-cyanophenyl)-1^5-pyrazolyl]-3-{8-{3,4 dihydro- 5- [2- (4-morphinolinyl)ethoxy] - ² ^chromenyl}} Urea

采用实施例 8 的制备方法，将其中的中间体 12 改为中间体 27, 得到标题化合物，为白色固体。 The title compound was obtained as a white solid.

'H-NMR (CDC1₃, 400MHz ) δ: 7.63-7.70 (m, 5H) , 7.18 (s， 1H)， 6.96 (s, 1H)， 6.40 (s, 1H)， 6.35 (d, 1H， /=9.2 Hz), 4.08-4.11 (m, 4H) , 3.73 (t, 4H, 7=4.4 Hz)， 2.84 (t, 2H)， 2.61-2.65 (m, 6H)， 1.95 (p, 2H), 1.35 (s, 9H)。 'H-NMR (CDC1 ₃ , 400MHz ) δ: 7.63-7.70 (m, 5H) , 7.18 (s, 1H), 6.96 (s, 1H), 6.40 (s, 1H), 6.35 (d, 1H, /= 9.2 Hz), 4.08-4.11 (m, 4H), 3.73 (t, 4H, 7=4.4 Hz), 2.84 (t, 2H), 2.61-2.65 (m, 6H), 1.95 (p, 2H), 1.35 ( s, 9H).

MS (FAB) m/z: 545.3 [M+l]⁺ ₀ 实施例 39: l-[3-叔丁基 -l-(3-氯 -4-氟苯基）- 1^5-吡唑基] -3 {8-{3, 4-二氢- 5- [2- (4-***啉基）乙氧基] - 2^·色烯基 }} 脲 MS (FAB) m/z: 545.3 [M+l] ⁺ ₀ Example 39: l-[3-tert-butyl-l-(3-chloro-4-fluorophenyl)-1^5-pyrazolyl ] -3 {8-{3, 4-Dihydro-5-[2-(4-morphinolinyl)ethoxy]-2^·Alkenyl}} Urea

采用实施例 8 的制备方法，将其中的中间体 12 改为中间体 23, 得到标题化合物，为白色固体。 The title compound was obtained as a white solid.

^-NMR (CDCI3, 400MHz ) δ 7.59 (m， 2H), 7.36 (m, 1H), 7.10 - 7.14 (m， 2H) , 6.88 (s, 1H) , 6.33-6.36 (m, 2H) , 4.08-4.11 (m, 4H) , 3.72 (t, 4H, /=4.0 Hz), 2.81 (t, 2H)， 2.61-2.64 (m, 6H), 1.93 (p, 2H), 1.34 (s, 9H)。 ^-NMR (CDCI3, 400MHz) δ 7.59 (m, 2H), 7.36 (m, 1H), 7.10 - 7.14 (m, 2H), 6.88 (s, 1H), 6.33-6.36 (m, 2H) , 4.08- 4.11 (m, 4H), 3.72 (t, 4H, /=4.0 Hz), 2.81 (t, 2H), 2.61-2.64 (m, 6H), 1.93 (p, 2H), 1.34 (s, 9H).

MS (FAB) m/z: 572.2 [M+l]⁺„ 实施例 40 : l-[3-叔丁基 -l-(4-甲基苯基）- 1H-5-吡唑基]- ³-〖⁸- (⁵- [ (⁴-甲氧基苯基）甲氧基] -²^色烯基 }}脲 MS (FAB) m / z: 572.2 [M + l] + " Example 40: l- [3- tert-butyl -l- (4- methylphenyl) - 1H-5- pyrazolyl] ^--3 - [ ⁸ - ( ⁵ - [ ( ⁴ - methoxyphenyl) methoxy] - ² ^ alkenyl}} urea

中间体 62 ( 617mg, 2mmol )溶于 25mL乙酸乙酯和 mL乙醇，分 4比加入二水合氯化亚锡（ 1.80g, 8mmol ) ，反应液变混浊，加热回流 8小时，冷却，加入饱和碳酸氢钠溶液，直至出现明显分层，分液， 7j层用乙酸乙酯提取 2次，合并有机层，用饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得到 541mg还原产物，收率 95%。 Intermediate 62 (617 mg, 2 mmol) was dissolved in 25 mL of ethyl acetate and ethyl acetate, and stannous chloride dihydrate (1.80 g, 8 mmol) was added in 4 portions. The reaction mixture became cloudy and added. The mixture was refluxed for 8 hours, cooled, and then added with a saturated aqueous solution of sodium bicarbonate, and the mixture was separated, and the mixture was separated, and the mixture was partitioned with ethyl acetate. The organic layer was combined, washed with brine, dried over anhydrous sodium sulfate and filtered. Concentration gave 541 mg of the reduced product in a yield of 95%.

在 lOOmL三口瓶中加入 30mL干燥的二氯甲烷，冷却到 - 1(TC，加入三光气（ 208mg, 0.70mmol ) , 慢慢滴加上步的得到的产物 (541mg, 1.9 mmol)溶于 20mL干燥二氯甲烷的溶液，有白色沉淀产生，反应 1小时，滴加 1. OmL干燥的三乙胺，沉淀溶解。加入中间体 11 (261mg, 1.14mmol) , 升温至室温，反应 5天，倒入 50mL水中，用二氯甲綻提取 3次，有机层用饱和食盐水洗涤，无水硫酸钠干燥，柱分离（洗脱体系：石油醚 /乙酸乙酯 =1:1)得到标题化合物 350mg，为白色晶体，收率 34.2%。 Add 30 mL of dry dichloromethane to a 100 mL three-necked flask, cool to -1 (TC, add triphosgene (208 mg, 0.70 mmol), and slowly add dropwise the obtained product (541 mg, 1.9 mmol) in 20 mL dry. A solution of methylene chloride was obtained as a white precipitate. After 1 hour, 1 mL of dry triethylamine was added dropwise, and the precipitate was dissolved. Intermediate 11 (261 mg, 1.14 mmol) was added, and the mixture was warmed to room temperature, and reacted for 5 days. In 50 mL of water, the mixture was extracted with chloroform, and the organic layer was washed with EtOAc (EtOAc) White crystals, yield 34.2%.

'H-NMR ( CDC1₃ , 400MHz ) δ： 7.68 (d, 1H， 7=8.8 Hz), 7.32-7.35 (m, 4H) , 7.17 (m, 2H)， 6.91 (d, 2H, =8.8 Hz), 6.77 (d, 1H)， 6.46 (d, 1H， 7=9.2 Hz) , 6.36 (s, 1H) , 5.68 (m, 1H)， 4.95 (t, 2H)， 4.68 (t, 2H， J .6 Hz), 3.83 (s, 3H) , 2.33 (s 3H), 1.35 (s, 9H)。 'H-NMR (CDC1 ₃ , 400MHz ) δ: 7.68 (d, 1H, 7=8.8 Hz), 7.32-7.35 (m, 4H), 7.17 (m, 2H), 6.91 (d, 2H, =8.8 Hz) , 6.77 (d, 1H), 6.46 (d, 1H, 7=9.2 Hz), 6.36 (s, 1H), 5.68 (m, 1H), 4.95 (t, 2H), 4.68 (t, 2H, J .6 Hz), 3.83 (s, 3H), 2.33 (s 3H), 1.35 (s, 9H).

MS (FAB) m/z: 526.2 [M+l]+。实施例 41 : l-[3-叔丁基 -1- (4-甲基苯基） -1H- 5-吡唑基〗 -3- {8- [5- (4-***啉基酰基甲氧基) - ²^色烯基] }脲 MS (FAB) m/z: 526.2 [M+l]+. Example 41: l-[3-tert-Butyl-1-(4-methylphenyl)-1H- 5-pyrazolyl-3-(8-[8-[5-(4-morphinolinyl methoxy) Base) - ² ^ alkenyl] urea

采用实施例 36的制备方法，将其中的中间体 50改为中间体 59，'得到标题化合物，为白色固体。 The title compound was obtained as a white solid.

^XH-NMR( CDC1₃, 400MHz ) δ: 7.76 (d, 1H, 7=9.2 Hz) , 7.34 (d 2H， 7=8.4 Hz), 7.22(d, 2H)， 6.72 (d, 1H， 7=10.0 Hz), 6.35-6.38 (m, 2H) , 5.73(m, 1H)， 4.71 (s, 2H)， 4.64(s， 2H) , 3.55-3.67 (m, 8H)， 2.36 (s, 3H) , 1.36 (s, 9H)。 MS (FAB) m/z: 546.2 [M+l]⁺ ₀ 实施例 42： l-[3-叔丁基 -l-(4-氟苯基）- 1^"5-吡唑基] -3- {8- {⁵- [2- (4-***啉基）乙氧基] -²^"色烯基 H脲 ^X H-NMR ( CDC1 ₃ , 400 MHz ) δ: 7.76 (d, 1H, 7 = 9.2 Hz), 7.34 (d 2H, 7 = 8.4 Hz), 7.22 (d, 2H), 6.72 (d, 1H, 7= 10.0 Hz), 6.35-6.38 (m, 2H), 5.73 (m, 1H), 4.71 (s, 2H), 4.64 (s, 2H), 3.55-3.67 (m, 8H), 2.36 (s, 3H), 1.36 (s, 9H). MS (FAB) m/z: 546.2 [M+l] ⁺ ₀ Example 42: l-[3-tert-butyl-l-(4-fluorophenyl)-1^"5-pyrazolyl] -3 - {8- { ⁵ - [2- (4-morphinolinyl)ethoxy] - ² ^" alkenyl H-urea

采用实施例 36的制备方法，将其中的中间体 11改为中间体 14, 得到标题化合物，为白色固体。 The title compound was obtained as a white solid.

'H-NMRCCDCls, 400MHz ) δ: 7.67 (d, 1H， 7=8.4 Hz) , 7.43(m, 2H)， 7.07-7.11 (m， 3H) , 6.73 (d, 1H， 7=10.4 Hz), 6.58 (s, IH) , 6.38 (d, 1H， 7=9.2 Hz), 6.35 (s, IH) , 5.73 (m, IH), 4.71 (t, 2H， 7=2.0 Hz) , 4.11 (t, 2H, /=5.2 Hz) , 3.75 (t, 4H) , 2.83(t, 2H), 2.61 (t, 4H), 1.35 (s, 9H)。 'H-NMRCCDCls, 400MHz) δ: 7.67 (d, 1H, 7=8.4 Hz), 7.43(m, 2H), 7.07-7.11 (m, 3H), 6.73 (d, 1H, 7=10.4 Hz), 6.58 (s, IH), 6.38 (d, 1H, 7=9.2 Hz), 6.35 (s, IH), 5.73 (m, IH), 4.71 (t, 2H, 7=2.0 Hz), 4.11 (t, 2H, /=5.2 Hz) , 3.75 (t, 4H), 2.83(t, 2H), 2.61 (t, 4H), 1.35 (s, 9H).

MS (FAB) m/z: 536.2 [M+l]⁺„ 实施例 43： 1-[3-叔丁基 -1- (4-氯苯基 )-lJ?-5-吡唑基] -3- {8- {5- [2- (4 -***啉基）乙氧基] - 2^"色烯基 }}脲 MS (FAB) m/z: 536.2 [M+l] ^<""""&&&&&&&&&&&&&&&&&&&&& - {8- {5- [2-(4- morphinyl)ethoxy] - 2^"alkenyl}}urea

采用实施例 36的制备方法，将其中的中间体 11改为中间体 15，得到标题化合物，为白色固体。 The title compound was obtained as a white solid.

^-NMRCCDC^, 400MHz ) δ: 7.65 (d, 1H， 7=8.8 Hz) , 7.43(d, 2H), 7.35 (d, 2H, 7=8.8 Hz), 7.10(s, IH) , 6.74 (d, IH, 7=10.0 Hz), 6.68 (s, IH), 6.36- 6.38 (m, 2H) , 5.72 (m, 1H)， 4.69 (t, 2H, 7=2.0 Hz) , 4.10(t, 2H, 7=5.2 Hz) , 3.74 (t, 4H, /=4.4 Hz) , 2.81 (t, 2H, 7=4.8 Hz), 2.59(t， 4H) , 1.35 (s, 9H)。 ^-NMRCCDC^, 400MHz) δ: 7.65 (d, 1H, 7=8.8 Hz), 7.43(d, 2H), 7.35 (d, 2H, 7=8.8 Hz), 7.10(s, IH) , 6.74 (d , IH, 7=10.0 Hz), 6.68 (s, IH), 6.36- 6.38 (m, 2H), 5.72 (m, 1H), 4.69 (t, 2H, 7=2.0 Hz), 4.10(t, 2H, 7=5.2 Hz), 3.74 (t, 4H, /=4.4 Hz), 2.81 (t, 2H, 7=4.8 Hz), 2.59(t, 4H), 1.35 (s, 9H).

MS (FAB) m/z: 552.2 [M+l]⁺ ₀ 实施例 44： 1- [3-叔丁基 - 1-(4-溴苯基 )-1^5-吡唑 ] -3- {8- {5- [2- (4 -***啉基）乙氧基] - 2 色烯基 }}脲 MS (FAB) m/z: 552.2 [M+l] ⁺ ₀ Example 44: 1-[3-tert-butyl-1-(4-bromophenyl)-1^5-pyrazole] -3- 8-{5- [2-(4- morphinolinyl)ethoxy]-2 alkenyl}}urea

采用实施例 36的制备方法，将其中的中间体 11改为中间体 16，得到标题化合物，为白色固体。 Using the preparation method of Example 36, the intermediate 11 was changed to an intermediate. 16. The title compound was obtained as a white solid.

'H-N RCCDC^, 400MHz ) δ: 7.65 (d, 1H)， 7.50(d, 2H， 7=8.8 Hz), 7.36 (d, 2H， /-8.8 Hz)， 7.12(s, IH), 6.77(s, IH) , 6.73(d 1H， 7=10.4 Hz), 6.38 (d, IH, 7.2 Hz)， 6.36 (s, IH)， 5.72(m, IH), 4.69(t, 2H, /=1.6 Hz), 4.10(t, 2H, 6 Hz)， 3.74(t, 4H, 7=4.4 Hz), 2.82 (t, 2H, 7=4.8 Hz), 2.60(t, 4H), 1.34 (s, 9H)。 'HN RCCDC^, 400MHz) δ: 7.65 (d, 1H), 7.50(d, 2H, 7=8.8 Hz), 7.36 (d, 2H, /-8.8 Hz), 7.12(s, IH), 6.77(s , IH), 6.73 (d 1H, 7 = 10.4 Hz), 6.38 (d, IH, 7.2 Hz), 6.36 (s, IH), 5.72 (m, IH), 4.69 (t, 2H, /=1.6 Hz) , 4.10(t, 2H, 6 Hz), 3.74(t, 4H, 7=4.4 Hz), 2.82 (t, 2H, 7=4.8 Hz), 2.60(t, 4H), 1.34 (s, 9H).

MS (FAB) m/z: 598.0 [M+l]^÷ _c 实施例 45: l-( 3-叔丁基 - 1-苯基 -1^·5-吡唑基）-3-{8-{5-U- (4 - ***啉基）乙氧基] - 2^色烯基 }}脲 MS (FAB) m/z: 598.0 [M+l] ^÷ _c Example 45: l-( 3-tert-butyl-1-phenyl-1^·5-pyrazolyl)-3-{8-{ 5-U-(4-morphinolinyl)ethoxy]-2^enyl}}urea

采用实施例 36的制备方法，将其中的中间体 11改为中间体 12，得到标题化合物，为白色固体。 The title compound was obtained as a white solid.

'H-NMRC CDC1₃, 400MHz ) δ: 7.71 (d， IH, /=8.8 Hz)， 7.45 (d, 2H)， 7.40 (t, 2H)， 7.29 (t, IH)， 7.20(s, IH)， 6.72 (d, IH, 7=10.0 Hz), 6.69(s， IH)， 6.36-6.38 (m, 2H)， 5.71 (m, 1H)， 4.69 (t, 2H， 7=2.0 Hz) , 4.09 (t, 2H)， 3.73(t, 4H, 7=4.4 Hz) , 2.81 (t, 2H, 7=5.2 Hz) , 2.59 (t, 4H)， 1.36 (s, 9H)。 'H-NMRC CDC1 ₃ , 400MHz ) δ: 7.71 (d, IH, /=8.8 Hz), 7.45 (d, 2H), 7.40 (t, 2H), 7.29 (t, IH), 7.20(s, IH) , 6.72 (d, IH, 7=10.0 Hz), 6.69(s, IH), 6.36-6.38 (m, 2H), 5.71 (m, 1H), 4.69 (t, 2H, 7=2.0 Hz), 4.09 ( t, 2H), 3.73 (t, 4H, 7 = 4.4 Hz), 2.81 (t, 2H, 7 = 5.2 Hz), 2.59 (t, 4H), 1.36 (s, 9H).

MS (FAB) m/z: 518.1 [M+l〗⁺。实施例 46: 1 - [3-叔丁基 -1- (4~甲氧基苯基） -li?~5-吡唑基] -3- {8 - {5- [2- (4 -***啉基）乙氧基] -2^~色烯基 }}脲 MS (FAB) m/z: 518.1 [M+l〗 ⁺ . Example 46: 1 - [3-tert-Butyl-1-(4-methoxyphenyl)-li?~5-pyrazolyl]-3-{8-{5-[2-(4-morphine) Phenyl)ethoxy] -2^~alkenyl}}urea

采用实施例 36的制备方法，将其中的中间体 11改为中间体 13, 得到标题化合物，为白色固体。 The title compound was obtained as a white solid.

Hz), 7.33 (d, 2H， 7=9.2 Hz) , 7.25 (s, 1H)， 6.88 (d, 2H， /=9.2 Hz) , 6.75(d, IH), 6.73 (s, 1H)， 6.36 (d, 1H)， 6.33 (s， IH), 5.70 (m, IH) , 4.67 (t, 2H， /=1.6 Hz), 4.10 (t, 2H)， 3.77 (s, 3H)， 3.74 (t, 4H, 7=4.4 Hz) , 2.80(t, 2H， /=5.6 Hz) , 2.59(t, 4H) , 1.35 (s, 9H)。

Hz), 7.33 (d, 2H, 7=9.2 Hz), 7.25 (s, 1H), 6.88 (d, 2H, /=9.2 Hz), 6.75(d, IH), 6.73 (s, 1H), 6.36 ( d, 1H), 6.33 (s, IH), 5.70 (m, IH), 4.67 (t, 2H, /=1.6 Hz), 4.10 (t, 2H), 3.77 (s, 3H), 3.74 (t, 4H, 7=4.4 Hz), 2.80(t, 2H, /=5.6 Hz), 2.59(t, 4H), 1.35 (s, 9H).

MS (FAB) m/z: 548.1 [M+l]⁺。实施例 47: l-[3-叔丁基三氟甲基苯基）-1 5-吡唑基] 3- {8- {5- [2 （4-***啉基）乙氧基〗色烯基 }}脲 MS (FAB) m/z: 548.1 [M+l] ⁺ . Example 47: l-[3-tert-Butyltrifluoromethylphenyl)-1 5-pyrazolyl] 3-{8-{5-[2 (4-morphinolinyl)ethoxy]chromene Urea

采用实施例 36的制备方法，将其中的中间体 11改为中间体 26，得到标题化合物，为白色固体。 The title compound was obtained as a white solid.

'H-N R (CDC1₃, 400MHz ) δ: 7· 65 (m， 5Η) , 7.07 (s, IH)， 6.76 (s, IH), 6.73(d, IH, 7=9.6 Hz) , 6.40(s, IH)， 6.38 (d， IH, /=8.8 Hz), 5.70 (m, IH)， 4.70 (t, 2H， 1=1.6 Hz), 4.10(t, 2H, 7=5.2 Hz) , 3.74 (t, 4H, 7=4.0 Hz) , 2.82 (t, 2H) , 2.60(t, 4H), 1.36 (s, 9H)。 'HN R (CDC1 ₃ , 400MHz ) δ: 7· 65 (m, 5Η) , 7.07 (s, IH), 6.76 (s, IH), 6.73 (d, IH, 7=9.6 Hz), 6.40(s, IH), 6.38 (d, IH, /=8.8 Hz), 5.70 (m, IH), 4.70 (t, 2H, 1 = 1.6 Hz), 4.10(t, 2H, 7=5.2 Hz), 3.74 (t, 4H, 7=4.0 Hz), 2.82 (t, 2H), 2.60(t, 4H), 1.36 (s, 9H).

MS (FAB) m/z: 586.1 [M+l]⁺ ₀ 实施例 48 : 1- [3-叔丁基 -l-(4-硝基苯基）- 1^-5-吡唑基] - 3- {8- {5- [2- (4-***啉基）乙氧基] 色烯基 }}脲 MS (FAB) m/z: 586.1 [M+l] ⁺ ₀ Example 48: 1-[3-tert-butyl-l-(4-nitrophenyl)-1^-5-pyrazolyl] 3-{8- {5- [2-(4-morphinolinyl)ethoxy]chromenyl}}urea

采用实施例 36的制备方法，将其中的中间体 11改为中间体 17, 得到标题化合物，为黄色固体。 The title compound was obtained as a yellow solid.

'H-NMRC CDCI3, 400MHz ) δ: 8.18 (d, 2H, /=9.2 Hz) , 7.74 (d, 2H, /=8.8 Hz) , 7.55 (d, IH)， 7.30 (s, IH)， 6.71 (d, 1H， /=10.0 Hz), 6.39 (s, 1H)， 6.34 (d, IH, 7=9.2 Hz)， 5.70 (m, IH) , 4.68(t, 2H, 6 Hz), 4.09 (t, 2H, /=6.0 Hz) , 3.74 (t, 4H, 7=4.4 Hz) , 2.81 (t, 2H, 7=6.0 Hz) , 2.60(t, 4H) , 1.34 (s, 9H)。 'H-NMRC CDCI3, 400MHz) δ: 8.18 (d, 2H, /=9.2 Hz), 7.74 (d, 2H, /=8.8 Hz), 7.55 (d, IH), 7.30 (s, IH), 6.71 ( d, 1H, /=10.0 Hz), 6.39 (s, 1H), 6.34 (d, IH, 7=9.2 Hz), 5.70 (m, IH), 4.68(t, 2H, 6 Hz), 4.09 (t, 2H, /=6.0 Hz), 3.74 (t, 4H, 7=4.4 Hz), 2.81 (t, 2H, 7=6.0 Hz), 2.60(t, 4H), 1.34 (s, 9H).

MS (FAB) m/z: 563.0 [M+l]⁺„ 实施例 49 : l-[3-叔丁基 - 1-(4-腈基苯基） -I 5-吡唑基]- 3- {8- {5- [2- (4-***啉基）乙氧基] - 2^色烯基 }}脲 MS (FAB) m/z: 563.0 [M+l] ⁺ „ Example 49: l-[3-tert-butyl-1-(4-cyanophenyl)-I 5-pyrazolyl]- 3-{8- {5-[2-(4-morphinolinyl) Ethoxy] - 2^-alkenyl}}urea

采用实施例 36的制备方法，将其中的中间体 11改为中间体 27，得到标题化合物，为白色固体。 The title compound was obtained as a white solid.

^-N R (CDC1₃, 400MHz ) δ: 7.64-7.70 (m, 5H), 7.15 (s, 1H)， 7.05 (s, IH), 6.74 (d, IH, 7=10.0 Hz), 6.40(s, IH)， 6.38 (d, 1H， 7-8.8 Hz), 5.73 (m, IH), 4.71 (t, 2H, /=1.6 Hz), 4. ll(t, 2H, 7=4.4 Hz) , 3.74(t， 4H, 7=4.8 Hz) , 2.83(t, 2H) , 2.61 (t, 4H), 1.34 (s, 9H)。 ^-NR (CDC1 ₃ , 400MHz ) δ: 7.64-7.70 (m, 5H), 7.15 (s, 1H), 7.05 (s, IH), 6.74 (d, IH, 7=10.0 Hz), 6.40(s, IH), 6.38 (d, 1H, 7-8.8 Hz), 5.73 (m, IH), 4.71 (t, 2H, /=1.6 Hz), 4. ll(t, 2H, 7=4.4 Hz), 3.74( t, 4H, 7=4.8 Hz), 2.83(t, 2H), 2.61 (t, 4H), 1.34 (s, 9H).

MS (FAB) m/z: 543.1 [M+l]+。实施例 50 : l-[3-叔丁基 1- (4-甲基苯基）- 1H-5 吡唑基〗-3-{8-{5-[2-(1-1， 2, 4-三氮唑基）乙氧基 ]-2^色烯基 }}脲采用实施例 36的制备方法，将其中的中间体 65改为中间体 69，得到标题化合物，为白色固体。 MS (FAB) m/z: 543.1 [M+l]+. Example 50: l-[3-tert-butyl 1-(4-methylphenyl)-1H-5pyrazolyl-3-{8-{5-[2-(1-1, 2, 4 The title compound was obtained as a white solid. m.p.

^•-N R (CDCI3, 400MHz ) δ: 8.10(s, IH) , 7.86 (s, IH)， 7.83 (d, IH, /=8.0 Hz) , 7.38 (s, IH), 7.32 (d, 2H, /=8.4 Hz) , 7.18 (d, 2H), 6.39 (s, 1H)， 6.36 (d， IH), 6.29(d, 1H， 7=9.2 Hz), 5.47 (m, IH)， 4.55 (t, 2H， 7=4.8 Hz) , 4.44 (t, 2H)， 4.28 (t 2H， 7=4.8 Hz), 2.33 (s, 3H)， 1.35 (s, 9H)。 ^•-NR (CDCI3, 400MHz) δ: 8.10(s, IH) , 7.86 (s, IH), 7.83 (d, IH, /=8.0 Hz), 7.38 (s, IH), 7.32 (d, 2H, /=8.4 Hz) , 7.18 (d, 2H), 6.39 (s, 1H), 6.36 (d, IH), 6.29 (d, 1H, 7=9.2 Hz), 5.47 (m, IH), 4.55 (t, 2H, 7=4.8 Hz), 4.44 (t, 2H), 4.28 (t 2H, 7=4.8 Hz), 2.33 (s, 3H), 1.35 (s, 9H).

MS (FAB) m/z: 514.2 [M+l]⁺ ₀ 实施例 51 : l-[3-叔丁基 -1- (4-乙基苯基） -1^"5-吡唑 ] -3- {8- {5- [2- (4-***啉基）乙氧基〗 - 2 色烯基 }}脲 MS (FAB) m/z: 514.2 [M+l] ⁺ ₀ Example 51: l-[3-tert-butyl-1-(4-ethylphenyl) -1^"5-pyrazole] -3 - {8- {5- [2-(4-morphinolinyl)ethoxy]-2 alkenyl}}urea

采用实施例 36的制备方法，将其中的中间体 11改为中间体 24, 得到标题化合物，为白色固体。 The title compound was obtained as a white solid.

^JH-N R( CDCI3, 400MHz ) δ 7.74 (d, 1H， /=8.8 Hz) , 7.36 (d, 2H, 7=8.4 Hz) , 7.25 (d, 2H) , 7.14 (s, IH), 6.73 (d, 1H， 7=10.0 Hz), 6.35-6.40 (m, 3H) , 5.72 (m, IH)， 4.71 (t, 2H， /=2.0 Hz) , 4.12 (t, 2H), 3.75 (t, 4H)， 2.84 (t, 2H)， 2.62-2.68 (m, 6H) , 1.36 (s, 9H)， 1.22 (t, 3H)。 ^J HN R ( CDCI3, 400MHz ) δ 7.74 (d, 1H, /=8.8 Hz) , 7.36 (d, 2H, 7=8.4 Hz), 7.25 (d, 2H), 7.14 (s, IH), 6.73 (d, 1H, 7=10.0 Hz), 6.35-6.40 (m, 3H), 5.72 (m, IH), 4.71 (t, 2H, /=2.0 Hz), 4.12 (t, 2H), 3.75 (t, 4H), 2.84 (t, 2H), 2.62-2.68 (m, 6H), 1.36 (s, 9H), 1.22 (t, 3H).

MS (FAB) m/z: 546.0 [M+l]⁺。实施例 52: l-[3-叔丁基 -l-(4-叔丁基苯基） -1^5-吡唑基]- 3- {8- {5- [2- (4-***啉基）乙氧基] - 2^·色烯基 }}脲 MS (FAB) m/z: 546.0 [M+l] ⁺ . Example 52: l-[3-tert-Butyl-l-(4-tert-butylphenyl)-l^5-pyrazolyl]- 3-{8- {5- [2-(4-morpholine) Ethyloxy] - 2^·alkenyl}}urea

采用实施例 36的制备方法，将其中的中间体 11改为中间体 25, 得到标题化合物，为白色固体。 The title compound was obtained as a white solid.

'E-mU CDC1₃, 400MHz ) δ: 7.74 (d, 1H， /=9.2 Hz)， 7.34 (d, 2H), 7.26 (d, 2H)， 7.15 (s, IH) , 6.73 (d, 1H， /-10.0 Hz), 6.43 (s, IH), 6.39 (d, IH, 7=9.2 Hz) , 6.35 (s， IH), 5.72 (m， 1H)， 4.71 (t, 2H， /-2.0 Hz), 4.09 (t, 2H, 7=5.2 Hz) , 3.73 (t, 4H), 2.81 (t, 2H), 2.59 (t, 4H)， 1.36(s， 9H)， 1.24 (d, 3H)， 1.22 (d, 3H)。 'E-mU CDC1 ₃ , 400MHz ) δ: 7.74 (d, 1H, /=9.2 Hz), 7.34 (d, 2H), 7.26 (d, 2H), 7.15 (s, IH), 6.73 (d, 1H, /-10.0 Hz), 6.43 (s, IH), 6.39 (d, IH, 7=9.2 Hz), 6.35 (s, IH), 5.72 (m, 1H), 4.71 (t, 2H, /-2.0 Hz) , 4.09 (t, 2H, 7=5.2 Hz), 3.73 (t, 4H), 2.81 (t, 2H), 2.59 (t, 4H), 1.36(s, 9H), 1.24 (d, 3H), 1.22 ( d, 3H).

MS (FAB) m/z: 560.1 [M+l]⁺ ₀ 实施例 53: l-[3-叔丁基 - 1-(3-氯 -4-氟苯基）- 吡唑基] -3- {8- {5- [2- (4-***啉基）乙氧基] ²^色烯基 }}脲 MS (FAB) m/z: 560.1 [M+l] ⁺ ₀ Example 53: l-[3-tert-butyl-1-(3-chloro-4-fluorophenyl)-pyrazolyl]-3- {8- {5- [2-(4-morphinolinyl)ethoxy] ² ^-alkenyl}}urea

采用实施例 36的制备方法，将其中的中间体 11改为中间体 23，得到标题化合物，为白色固体。 The title compound was obtained as a white solid.

^-NMR (CDCI3, 400MHz ) δ: 7.60 (m, 2H), 7.38 (m, IH)， 7.08-7.14 (m, 3H)， 6.72 (d, 1H， /=9.6 Hz) , 6.38 (d, IH, 7=8.8 Hz), 6.35 (s, 1H)， 5.72 (m, 1H)， 4.70(t, 2H， /=1.6 Hz), 4.10(t 2H， 1=5.2 Hz) , 3.74 (t, 4H, 7=4.4 Hz) , 2.83(t， 2H)， 2.61 (t, 4H), 1.34 (s, 9H)。 MS (FAB) m/z: 570.0 [M+l]⁺ ₀ 实施例 54: l-[3_叔丁基 -l-(3， 4-二甲基苯基） -1^5-吡唑基] -3- {8- {5- [2- (4-***啉基）乙氧基] -2 色烯基 }}脲 ^-NMR (CDCI3, 400MHz) δ: 7.60 (m, 2H), 7.38 (m, IH), 7.08-7.14 (m, 3H), 6.72 (d, 1H, /=9.6 Hz), 6.38 (d, IH , 7=8.8 Hz), 6.35 (s, 1H), 5.72 (m, 1H), 4.70(t, 2H, /=1.6 Hz), 4.10(t 2H, 1=5.2 Hz), 3.74 (t, 4H, 7=4.4 Hz) , 2.83(t, 2H), 2.61 (t, 4H), 1.34 (s, 9H). MS (FAB) m/z: 570.0 [M+l] ⁺ ₀ Example 54: l-[3_tert-butyl-l-(3,4-dimethylphenyl) -1^5-pyrazolyl ] -3- {8- {5- [2-(4-morphinolinyl)ethoxy] -2 alkenyl}}urea

采用实施例 36的制备方法，将其中的中间体 11改为中间体 Using the preparation method of Example 36, the intermediate 11 was changed to an intermediate.

^- MR ( CDC1₃ , 400MHz ) δ： 7.72 (d, 1H, /=8.8 Hz), 7.12-7.21 (m, 4H), 6.72 (d, 1H， /=10.4 Hz)， 6.60 (s, IH)，^- MR ( CDC1 ₃ , 400MHz ) δ: 7.72 (d, 1H, /=8.8 Hz), 7.12-7.21 (m, 4H), 6.72 (d, 1H, /=10.4 Hz), 6.60 (s, IH) ,

6.38 (d, 1H)， 6.34 (s, IH) , 5.70(m, 1H)， 4.68 (t, 2H， 7=2.0 Hz), 4.10 (t, 2H, 1=5.6 Hz) , 3.74 (t, 4H, 4.4 Hz) , 2.82 (t, 2H， 7=5.6 Hz), 2.60(t, 4H)， 2.23 (s, 3H) , 2.21 (s, 3H) , 1.35 (s 9H)。 6.38 (d, 1H), 6.34 (s, IH), 5.70(m, 1H), 4.68 (t, 2H, 7=2.0 Hz), 4.10 (t, 2H, 1 = 5.6 Hz), 3.74 (t, 4H , 4.4 Hz), 2.82 (t, 2H, 7=5.6 Hz), 2.60(t, 4H), 2.23 (s, 3H), 2.21 (s, 3H), 1.35 (s 9H).

MS (FAB) m/z: 546.0 [M+l]⁺ ₀ 实施例 55: 1- [3-叔丁基 -l-(3， 4-二氯苯基） -1^"5-吡唑基] -3- {8- {5- [2 -（4-***啉基）乙氧基] -2^~色烯基 }}脲 MS (FAB) m/z: 546.0 [M+l] ^{+ &lt} _; "&&&&&&&&&&&&&&&&&&&& ] -3- {8- {5- [2- (4-morphinolinyl)ethoxy] -2^~chromenyl}}urea

'H-NMR (CDCI3, 400MHz ) δ: 7.67 (s, IH), 7.58 (d， IH)， 'H-NMR (CDCI3, 400MHz) δ: 7.67 (s, IH), 7.58 (d, IH),

7.45(s, 1H)， 7.38 (m, 2H), 7.23(s, IH)， 6.71 (d, 1H， 7=10.0 Hz), 6.36 (d, 1H， 7=9.2 Hz) , 6.35 (s, IH)， 5.69 (m, IH)， 4.68 (t 2H, 7=1.6 Hz), 4.10 (t, 2H, 7=5.6 Hz) , 3.73 (t, 4H, 7=4.8 Hz) , 2.82 (t, 2H, /=5.2 Hz)， 2.60(t, 4H) , 1.34 (s, 9H)。 7.45(s, 1H), 7.38 (m, 2H), 7.23(s, IH), 6.71 (d, 1H, 7=10.0 Hz), 6.36 (d, 1H, 7=9.2 Hz), 6.35 (s, IH ), 5.69 (m, IH), 4.68 (t 2H, 7=1.6 Hz), 4.10 (t, 2H, 7=5.6 Hz), 3.73 (t, 4H, 7=4.8 Hz), 2.82 (t, 2H, /=5.2 Hz), 2.60(t, 4H), 1.34 (s, 9H).

MS (FAB) m/z: 586.0 [M+l]⁺。实施例 56: 1- (3-叔丁基 - 5-异噁唑基) -³- {⁸ - {⁵- [²-(⁴-***啉基) 乙氧基] -² 色烯基 }}脲采用实施例 36的制备方法，将其中的中间体 11改为中间体 28, 得到标题化合物，为白色固体。 MS (FAB) m/z: 586.0 [M+l] ⁺ . Example 56: 1-(3-tert-Butyl 5- 5-oxazolyl) - ³ - { ⁸ - { ⁵ - [ ² -( ⁴ -morphinolinyl)ethoxy] - ² - alkenyl}} Urea The title compound was obtained as a white solid.

^JH-NMR (CDC 1₃, 400MHz ) δ: 9.27 (s, 1H)， 7.74 (d, IH, 7=8.8 Hz), 7.40 (s, IH), 6.67(d， 1H， 7=10.0 Hz), 6.37 (d, 1H， 7=9.2 Hz), 6.13(s， IH), 5.63(m, IH)， 4.62 (t， 2H， 7=1.6 Hz), 4.10(t， 2H， 7=5.6 Hz) , 3.77 (t, 4H， 7=4.4 Hz) , 2.83(t, 2H， 7=5.2 Hz) , 2.69 (t, 4H), 1.30(s, 9H)。 ^J H-NMR (CDC 1 ₃ , 400 MHz ) δ: 9.27 (s, 1H), 7.74 (d, IH, 7 = 8.8 Hz), 7.40 (s, IH), 6.67 (d, 1H, 7 = 10.0 Hz) , 6.37 (d, 1H, 7=9.2 Hz), 6.13(s, IH), 5.63(m, IH), 4.62 (t, 2H, 7=1.6 Hz), 4.10(t, 2H, 7=5.6 Hz) , 3.77 (t, 4H, 7 = 4.4 Hz), 2.83 (t, 2H, 7 = 5.2 Hz), 2.69 (t, 4H), 1.30 (s, 9H).

MS (FAB) m/z: 443.0 [M+l]+。实施例 57: 1- (5-叔丁基 -3-异嚙唑基) -3- {8- {5- [2- (4-***啉基) 乙氧基] -2^色烯基 }}脲 MS (FAB) m/z: 443.0 [M+l]+. Example 57: 1-(5-tert-Butyl-3-isoxazolyl)-3-{8-{5-[2-(4-morphinolinyl)ethoxy]-2^-alkenyl} Urea

釆用实施例 36的制备方法，将其中的中间体 11改为 3-氨基 -5 -叔丁基异喁唑，得到标题化合物，为白色固体。 The title compound was obtained as a white solid.

'H-NMR (CDCls, 400MHz ) δ: 8.77 (s, IH), 8.27 (s, IH)， 7.86 (d, 1H， /=8.8 Hz) , 6.75 (d, 1H， 7=10.0 Hz), 6.42 (d, IH, /=9.6 Hz), 6.02(s， 1H)， 5.76 (m, IH), 4.84 (t, 2H， /-2.0 Hz), 4.12 (t, 2H, 1=6.8 Hz) , 3.76 (t, 4H) , 2.84 (t, 2H), 2.62 (t, 4H), 1.36 (s, 9H)。 'H-NMR (CDCls, 400MHz) δ: 8.77 (s, IH), 8.27 (s, IH), 7.86 (d, 1H, /=8.8 Hz), 6.75 (d, 1H, 7=10.0 Hz), 6.42 (d, IH, /=9.6 Hz), 6.02(s, 1H), 5.76 (m, IH), 4.84 (t, 2H, /-2.0 Hz), 4.12 (t, 2H, 1=6.8 Hz), 3.76 (t, 4H), 2.84 (t, 2H), 2.62 (t, 4H), 1.36 (s, 9H).

MS (FAB) m/z: 443.0 [M+l]⁺ ₀ 实施例 58 : 1- [ 叔丁基 -3-(4-曱基苯基） -1^4-吡唑基] -3- {8- {5- U- (4-***啉基）乙氧基] -²^~色烯基 H脲 MS (FAB) m/z: 443.0 [M+l] ⁺ ₀ Example 58: 1-[tert-butyl-3-(4-mercaptophenyl)-1^4-pyrazolyl]-3- 8- {5- U-(4-morphinolinyl)ethoxy] - ² ^~ alkenyl Hurea

采用实施例 36的制备方法，将其中的中间体 11改为中间体 33，得到标题化合物，为白色固体。 The title compound was obtained as a white solid.

ιΕ-ΜΠ CDC1₃, 400MHz ) δ: 7.67-7.70 (m, 2Η) , 7.18-7.20 (m, 4Η)， 6.73 (d, IH, 7=10.0 Hz), 6.68 (s, 1H)， 6.36 (d, 1H， 7=9.2 Hz), 5.72(m, IH)， 5.49 (s, 1H)， 4.71 (t, 2H, 1=2.0 Hz) , 4.11 (t, 2H), 3.76 (t, 4H)， 2.83(t， 2H)， 2.62 (t, 4H)， 2.39 (s, 3H)，ΕΕ-ΜΠ CDC1 ₃ , 400MHz ) δ: 7.67-7.70 (m, 2Η) , 7.18-7.20 (m, 4Η), 6.73 (d, IH, 7=10.0 Hz), 6.68 (s, 1H), 6.36 (d , 1H, 7=9.2 Hz), 5.72(m, IH), 5.49 (s, 1H), 4.71 (t, 2H, 1=2.0 Hz), 4.11 (t, 2H), 3.76 (t, 4H), 2.83(t, 2H), 2.62 (t, 4H), 2.39 (s, 3H),

1.46 (s, 9H)。 1.46 (s, 9H).

MS (FAB) m/z: 532.1 [M+l]⁺。实施例 59 : 1 - [3-叔丁基 - 1-(3-甲基苯基） -l 5-吡唑基] - 3- {8- {5- [2- (4-***啉基）乙氧基] -2^色烯基 }}脲 MS (FAB) m/z: 532.1 [M+l] ⁺ . Example 59: 1-[3-tert-butyl-1-(3-methylphenyl)-l 5-pyrazolyl]-3-(8-{5-[5-[2-(4-morphinolinyl)) Ethoxy] -2^ alkenyl}}urea

21, 得到标题化合物，为白色固体。 21, the title compound was obtained as a white solid.

'H-NMR ( CDCls, 400MHz ) δ： 7.22 (d, 1H， 7=8.8 Hz)， 7.26-7.29 (m, 3H)， 7.15(d， 2H), 6.73 (d, 1H， 7=10.0 Hz), 6.58 (s, 1H)， 6.38 (d, 1H， 7=9.6 Hz), 6.36 (s, 1H)， 5.72 (m, 1H)， 4.71(t, 2H, /=1.6Hz)， 4.12 (t, 2H) , 3.76 (t, 4H) , 2.84(t 2H)， 2.63(t, 4H)， 2.36 (s, 3H) , 1.36 (s, 9H)。 'H-NMR (CDCls, 400MHz) δ: 7.22 (d, 1H, 7=8.8 Hz), 7.26-7.29 (m, 3H), 7.15(d, 2H), 6.73 (d, 1H, 7=10.0 Hz) , 6.58 (s, 1H), 6.38 (d, 1H, 7=9.6 Hz), 6.36 (s, 1H), 5.72 (m, 1H), 4.71(t, 2H, /=1.6Hz), 4.12 (t, 2H), 3.76 (t, 4H), 2.84 (t 2H), 2.63 (t, 4H), 2.36 (s, 3H), 1.36 (s, 9H).

MS (FAB) m/z: 532.1 [ +l]⁺ ₀ 实施例 60 ： 1-[(3- 叔丁基 -1- 萘基）- 1^5- 吡唑基] -3- {8- {5- [2- (4-***啉基）乙氧基] - 2^色烯基 }}脲 MS (FAB) m/z: 532.1 [+l] ⁺ ₀ Example 60: 1-[(3-tert-butyl-1-naphthyl)-1^5-pyrazolyl]-3-{8- { 5-[2-(4-morphinolinyl)ethoxy]-2^enyl}}urea

^一履 R( CDCI3, 400MHz ) 5: 7.88-7.90 (m, 2H) , 7.48-7.50 (m_: 5Η)， 7.38 (d, 1Η)， 6.95 (s, 1Η), 6.68(d, 1H， /=10.0 Hz), 6.48(s, 1H)， 6.24-6.27 (m, 2H) , 5.67 (m, 1H), 4.63(t, 2H， /-1.6 Hz), 4.07 (t, 2H， 7=5.2 Hz), 3.75 (t, 4H, 7=4.4 Hz),^一履R(CDCI3, 400MHz) 5: 7.88-7.90 (m, 2H), 7.48-7.50 (m _: 5Η), 7.38 (d, 1Η), 6.95 (s, 1Η), 6.68(d, 1H, / =10.0 Hz), 6.48(s, 1H), 6.24-6.27 (m, 2H), 5.67 (m, 1H), 4.63(t, 2H, /-1.6 Hz), 4.07 (t, 2H, 7=5.2 Hz ), 3.75 (t, 4H, 7=4.4 Hz),

2.82 (t, 2H)， 2.61 (t, 4H)， 1.40(s, 9H)。 2.82 (t, 2H), 2.61 (t, 4H), 1.40(s, 9H).

MS (FAB) m/z: 568.1 [M+l]⁺„ 实施例 61 : l-[4-叔丁基 -1- (4-甲基苯基）- 1^~2-咪唑基] -3- {8 - {5- [2- (4-***啉基）乙氧基] - 2^·色烯基 } }脲采用实施例 36的制备方法，将其中的中间体 11改为中间体 35, 得到标题化合物，为白色固体。 MS (FAB) m/z: 568.1 [M+l] ^{+ <} /RTI></RTI> Example 61: l-[4-tert-butyl-1-(4-methylphenyl)- 1^~2-imidazole Benzyl]-3-{8-{5-[2-(4-morphinolinyl)ethoxy]-2^·enyl}}urea The preparation method of Example 36 was used to change the intermediate 11 The title compound was obtained as a white solid.

'H-NMR ( CDC1₃ , 400MHz ) δ： 8.03 (d, IH, /=9.2 Hz), 7.26-7.30 (m, 5H)， 6.78(d, 1H， 7=10.0 Hz), 6.44 (s, IH)， 6.41(d, IH, 1=9.2 Hz) , 5.77 (m, IH) , 4.88 (t， 2H)， 4.13(t, 2H， /-6.8 Hz), 3.76 (t, 4H)， 2.84 (t, 2H) , 2.62 (t, 4H) , 2.42 (s 3H)， 1.34 (s, 9H)。 'H-NMR ( CDC1 ₃ , 400MHz ) δ: 8.03 (d, IH, /=9.2 Hz), 7.26-7.30 (m, 5H), 6.78(d, 1H, 7=10.0 Hz), 6.44 (s, IH ), 6.41(d, IH, 1=9.2 Hz), 5.77 (m, IH), 4.88 (t, 2H), 4.13(t, 2H, /-6.8 Hz), 3.76 (t, 4H), 2.84 (t , 2H), 2.62 (t, 4H), 2.42 (s 3H), 1.34 (s, 9H).

MS (FAB) m/z: 532.4 [M+l]⁺ ₀ 实施例 62 : l-[3-叔丁基 - 1-(4-甲基苯基）- 1H-5-吡唑基]- 3-{8- {5- {2- [4 -（顺式 - 2, 6 -二甲基）***啉基]乙氧基 } -li 色烯基 }}脲 MS (FAB) m/z: 532.4 [M+l] ⁺ ₀ Example 62: l-[3-tert-butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]- 3 -{8- {5- {2- [4 -(cis- 2,6-dimethyl)morphinolinyl]ethoxy}-li color alkenyl}}urea

釆用实施例 36的制备方法，将其中的中间体 50改为中间体 66, 得到标题化合物，为白色固体。 The title compound was obtained as a white solid.

^JH-NMR (CDC1₃, 400MHz ) δ: 7.74 (d, IH, 7=9.2 Hz) , 7.33 (d, 2H, /-8.0 Hz), 7.22 (d, 2H), 7.14 (s, IH), 6.74 (d, IH, 7=10.0 Hz), 6.45(s, IH), 6.39 (d, 1H， /=9.2 Hz) , 6.35 (s, IH)， 5.72 (m_: IH), 4.71(t, 2H, 7=1.6 Hz), 4.12 (t, 2H， 7=4.0 Hz), 3.74 (m, 2H)， 2.83(m, 4H) , 2.36 (s， 3H) , 1.94 (m, 2H) , 1.36 (s， 9H)， 1.17 (d, 3H), 1.16 (d, 3H)。 ^J H-NMR (CDC1 ₃ , 400MHz ) δ: 7.74 (d, IH, 7=9.2 Hz), 7.33 (d, 2H, /-8.0 Hz), 7.22 (d, 2H), 7.14 (s, IH), 6.74 (d, IH, 7=10.0 Hz), 6.45(s, IH), 6.39 (d, 1H, /=9.2 Hz), 6.35 (s, IH), 5.72 (m _: IH), 4.71(t, 2H , 7=1.6 Hz), 4.12 (t, 2H, 7=4.0 Hz), 3.74 (m, 2H), 2.83 (m, 4H), 2.36 (s, 3H), 1.94 (m, 2H), 1.36 (s , 9H), 1.17 (d, 3H), 1.16 (d, 3H).

S (FAB) m/z: 532.4 [M+l]⁺。 S (FAB) m/z: 532.4 [M+l] ⁺ .

Claims

1. 通式 I化合物，其可药用盐或溶剂化物， A compound of formula I, a pharmaceutically acceptable salt or solvate thereof,

I I

其中： among them:

入^为^- 。芳香碳环或 C₃- 。饱和或不饱和的非芳香碳环； C -C。芳香杂环，包括一到多个选自 0, N, S的杂原子；或者 C₅-C₈ 的单杂环或者 C₈- 的双杂环，包括一到多个选自 0, N, S的杂原子；所述 A 独立并选择性地被一到多个 11₂所取代； Enter ^ as ^-. Aromatic carbon ring or C ₃ - . Saturated or unsaturated non-aromatic carbon ring; C-C. An aromatic heterocyclic ring comprising one or more heteroatoms selected from 0, N, S; or a C ₅ -C ₈ monoheterocyclic ring or a C ₈ -biheterocyclic ring comprising one or more selected from the group consisting of 0, N, a hetero atom of S; said A is independently and selectively substituted by one to more 11 ₂ ;

Ar₂为苯并五元或六元杂环。当为五元杂环时，环上包括 1-3 个选自 0, N， S的杂原子；当为六元杂环时，环上有一个选自 0， S 的杂原子或 2-4个选自 0, N， S的杂原子；所述 Ar₂可选择性被 1-4 个选自下面的取代基取代： C!-C^直链或支链烷基， C₂-C_fi直链或支链烯基， d- 直链或支链烷氧基， C₂-C₆直链或支链烯氧基，三氟曱基，三氟甲氧基，乙酰基，芳酰基，鹵素，甲氧叛基，乙氧羰基，苯磺酰基，羟基，氨基，单或双 d- C₄烷基取代的氨基，单或双(^-(：₄烷基取代的氨基磺酰基，腈基，硝基，氨基磺酰基； Ar ₂ is a benzo five- or six-membered heterocyclic ring. When it is a five-membered heterocyclic ring, the ring includes 1-3 heteroatoms selected from 0, N, S; when it is a six-membered heterocyclic ring, the ring has a hetero atom selected from 0, S or 2-4 a hetero atom selected from 0, N, S; the Ar ₂ may be optionally substituted with from 1 to 4 substituents selected from C:-C^ straight or branched alkyl, C ₂ -C _fi Linear or branched alkenyl, d-linear or branched alkoxy, C ₂ -C ₆ straight or branched alkenyloxy, trifluoromethyl, trifluoromethoxy, acetyl, aroyl, Halogen, methoxyhistyl, ethoxycarbonyl, phenylsulfonyl, hydroxy, amino, mono or di-d-C ₄ alkyl substituted amino, mono or bis(^-(: ₄ alkyl substituted aminosulfonyl, nitrile Base, nitro, aminosulfonyl;

L独立的为 L independent

( 1 )键; (1) key;

( 2 ) d-Ci。饱和或不饱和的，直链或支链碳链；其中的一到多个亚甲基独立并选择性被 0, NH， S ( 0 ) _a或者 0-2个羰基所替代；并且所述联接基团可选择性被一到多个卤原子取代； m为 0， 1或 2; (2) d-Ci. a saturated or unsaturated, linear or branched carbon chain; wherein one or more methylene groups are independently and selectively replaced by 0, NH, S ( 0 ) _a or 0-2 carbonyl groups; The group may be optionally substituted with one or more halogen atoms; m is 0, 1 or 2;

P为咪唑基，噁唑基，异喁唑基，噻唑基，异噻唑基，吡咯基，苯并咪唑基，呋喃基，噻吩基，吡喃基，萘啶基，哌嗪基，吡唑基，噻基，嘌呤基，吡唑并 [3， 4-b]嘧啶基，吡咯并 [2 , 3 - b〗吡啶基，吡咯并 [3， 4-b]吡啶基， 1， 3-氧氮杂并 [4 , 5-b]吡啶基， 1 , 2， 3-三氮唑基， 1 , 2， 4-三氮唑基，四氮唑基，四氢吡喃基，四氢呋喃基，二氢萘基，四氢萘基，二氢奎啉基，四氢喹啉基，二氢异喹啉基，四氢异喹啉基， 1 , 3-二氧环戊酮基， 1 , 3-二氧环己酮基， 1， 4-二氧六环基，吗啉基，硫代吗啉基，亚砜代吗啉基，砜代吗啉基，哌啶基，哌啶酮基，哌啶醇基，四氢嘧啶酮基，环己酮基，环己醇基，硫杂己环基，五亚甲基亚砜基，五亚甲基砜基，四氢噻吩基，四亚甲基亚砜基，四亚甲基砜基；所述基团可任选被 1-3个选自下面的取代基取代： d- C₆直链或支链烷基， C₂-C₆直链或支链烯基， d- 直链或支链烷氧基， C₂-C₆直链或支链烯氧基，三氟甲基，三氟甲氧基，乙酰基，芳酰基，卤素，苯磺酰基，羟基，氨基，单或双 d- C₄¾基取代的氨基，单或双 (；广烷基取代的氨基酰基， d- 烷氧羰基， d-C₅酰氧基，单或双 C广 (：₄烷基取代的氨基磺酰基，腈基，硝基，氨基磺酰基； P is imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, benzimidazolyl, furyl, thienyl, pyranyl, naphthyridinyl, piperazinyl, pyrazolyl , thiol, fluorenyl, pyrazolo[3,4-b]pyrimidinyl, pyrrolo[2,3 - b]pyridyl, pyrrolo[3,4-b]pyridyl, 1, 3-oxo Hetero[4,5-pyridinyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, tetrazolyl, tetrahydropyranyl, tetrahydrofuranyl, dihydrogen Naphthyl, tetrahydronaphthyl, dihydroquinolinyl, tetrahydroquinolyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, 1, 3-dioxocyclopentanone, 1, 3-di Oxycyclohexanone, 1, 4-dioxocyclo, morpholinyl, thiomorpholinyl, sulfoxide morpholino, sulfonylmorpholinyl, piperidinyl, piperidinone, piperidine Alcohol group, tetrahydropyrimidinone group, cyclohexanone group, cyclohexanol group, thiacyclohexyl group, pentamethylene sulfoxide group, pentamethylene sulfone group, tetrahydrothiophenyl group, tetramethylene group a sulfone group, a tetramethylene sulfone group; the group may be optionally selected from 1 to 3 selected from below Substituents: d- C ₆ linear or branched alkyl, C ₂ -C ₆ straight or branched alkenyl group, d- a straight-chain or branched alkoxy, C ₂ -C ₆ straight or branched chain Alkenyloxy, trifluoromethyl, trifluoromethoxy, acetyl, aroyl, halogen, benzenesulfonyl, hydroxy, amino, mono- or di-d-C _{4 3⁄4} -substituted amino, mono- or bi- Alkyl-substituted aminoacyl group, d-alkoxycarbonyl group, dC ₅ acyloxy group, mono- or di-C-wide (: ₄ alkyl-substituted aminosulfonyl group, nitrile group, nitro group, aminosulfonyl group;

R¹独立的为 R ^{1 is} independent

( 6 ) d- 。直链或支链烷基，所述烷基可部分或全部被卤代，并且可选择性被 1-3个苯基，萘基或以下的杂环取代：喹啉基，异喹啉基，吡啶基，嘧啶基，哒嗪基，哌嗪基，吡咯基，咪唑基，吡唑基，呋喃基，噻吩基，异喁唑基，异噻唑基；上述苯基，萘基或杂环可被 0-5个下述基团取代：卤素，（；广直链或支链烷基， 0；₃-( ₈环烷基， C₅-C^、烯基，羟基，腈基， C₆直链或支链垸氧基，三氟甲基，三氟甲氧基，氨基羰基，双 (广烷基取代的氨基羰基；(6) d-. a linear or branched alkyl group which may be partially or fully halogenated and optionally substituted with from 1 to 3 phenyl, naphthyl or a heterocyclic ring: quinolyl, isoquinolinyl, Pyridyl, pyrimidinyl, pyridazinyl, piperazinyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, isoxazolyl, isothiazolyl; the above phenyl, naphthyl or heterocyclic ring can be 0-5 of the following groups substituted: halogen, (; broad linear or branched alkyl, 0; _3- ( ₈ -cycloalkyl, C ₅ -C^, alkenyl, hydroxy, nitrile, C ₆ straight Chain or branched decyloxy, trifluoromethyl, trifluoromethoxy, aminocarbonyl, bis(polyalkyl substituted aminocarbonyl;

( 7 ) Cr^。环烷基或环烯基，所述基团可部分或全部被卤代，或选择性被 1-3个(^-(^烷基或 d-Cs烷氧基取代；上述的环烷基或环烯基的卜 3个亚甲基可选择性被 0, NH, S, SO, S0₂，藏基，羟甲基替代；上迷环烷基或环烯基可独立的选择性被 0-5个以下基团取代：卤素， d-Ce直链或支链烷基，（广直链或支链垸氧基；(7) Cr^. a cycloalkyl or cycloalkenyl group, said group being partially or fully halogenated Or, optionally, substituted by 1-3 (^-(^ alkyl or d-Cs alkoxy; the above methylene group of cycloalkyl or cycloalkenyl group may be selectively substituted by 0, NH, S, SO, S0 ₂ , Tibetan, hydroxymethyl substitution; cycloalkyl or cycloalkenyl can be independently substituted with 0-5 groups: halogen, d-Ce straight or branched alkane Base, (wide linear or branched decyloxy;

( 8 ) ( -C,。直链或支链烯基，所述垸基可部分或全部被卤代，并且可选择性被 1- 3个(^-(^直链或支链烷基，苯基，萘基或以下的杂环取代：喹啉基，异喹啉基，吡啶基，嘧啶基，哒嗪基，哌嗪基，吡咯基，咪唑基，吡唑基，呋喃基，噻吩基，异喁唑基，异噻唑基；上述苯基，萘基或杂环可被 0-5个下述基团取代：卤素， C Ce直链或支链烷基， C₃- 。环烷基， C广 (^环烯基，羟基，腈基， d-C₆直链或支链烷氧基，三氟甲基，三氟甲氧基，氨基羰基，双 d-O^基取代的氨基羰基； (8) (-C, a linear or branched alkenyl group, which may be partially or fully halogenated, and may be optionally one to three (^-(^ straight or branched alkyl groups, Phenyl, naphthyl or a heterocyclic ring substitution: quinolyl, isoquinolinyl, pyridyl, pyrimidinyl, pyridazinyl, piperazinyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl , isoxazolyl, isothiazolyl; the above phenyl, naphthyl or heterocyclic ring may be substituted by 0-5 groups: halogen, C Ce straight or branched alkyl, C ₃ - cycloalkyl , C ( (cycloalkenyl, hydroxy, nitrile, dC ₆ linear or branched alkoxy, trifluoromethyl, trifluoromethoxy, aminocarbonyl, bis dO ^ substituted aminocarbonyl;

( 9 ) 卤素，硝基，羧基，羟基，腈基，三氟甲基，三氟甲氧基； (9) halogen, nitro, carboxy, hydroxy, nitrile, trifluoromethyl, trifluoromethoxy;

( 10 ) NH₂-, R³NH~, R³ ₂N -， R³NCO-R³CONH-, R³C00-， R³0C0 -， R³S (0) _m, R³S (0) _mNH, R³NHS (0) - ； ( 10 ) NH ₂ -, R ³ NH~, R ³ ₂ N -, R ³ NCO-R ³ CONH-, R ³ C00-, R ³ 0C0 -, R ³ S (0) _m , R ³ S (0 _m NH, R ³ NHS (0) - ;

R²独立的为 R ² independent is

( 5 ) 芳环，芳杂环基或稠合芳环，包括苯基，萘基，喹啉基，异喹啉基，吡啶基，嘧啶基，哒嗪基，咪唑基，喁唑基，异喁唑基，噻唑基，异噻唑基，吡咯基，呋喃基，噻哈基，吡喃基，萘啶基，哌嗪基，吡唑基，噻唑基，嘌呤基，吲哚基，苯并咪唑基，苯并呋喃基，苯并吡唑基，苯并噻吩基，苯并喁唑基，苯并异喁峻基，苯并噻唑基，苯并异噻唑基，吡唑并 [3, 4-b]嘧啶基，吡咯并 [2， 3-b]吡啶基，吡咯并 [3, 4-b]吡啶基， 1， 3-氧氮杂并 [4， 5 - b]吡啶基， 1 , 2， 3-三氮唑基， 1， 2 , 4-三氮唑基，四氮唑基，四氢吡喃基，四氢呋喃基，二氢萘基，四氢萘基，二氢喹啉基，四氢喹啉基，二氢异喹啉基，四氢异喹啉基，苯并环丁基，茚基，茚烯基。上述芳环，芳杂环或稠合芳环基可独立的被 0-5 个 R⁴基团取代； (5) an aromatic ring, an aromatic heterocyclic group or a fused aromatic ring, including phenyl, naphthyl, quinolyl, isoquinolinyl, pyridyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, iso Carbazolyl, thiazolyl, isothiazolyl, pyrrolyl, furyl, thiahaki, pyranyl, naphthyridinyl, piperazinyl, pyrazolyl, thiazolyl, fluorenyl, fluorenyl, benzimidazole Benzofuranyl, benzopyrazolyl, benzothienyl, benzoxazolyl, benzisoindolyl, benzothiazolyl, benzisothiazolyl, pyrazolo[3, 4- b]pyrimidinyl, pyrrolo[2,3-b]pyridyl, pyrrolo[3,4-b]pyridinyl, 1, 3-oxathia[4,5-b]pyridyl, 1 , 2 , 3-triazolyl, 1, 2, 4-triazolyl, tetrazolyl, tetrahydropyranyl, tetrahydrofuranyl, dihydronaphthyl, tetrahydronaphthyl, dihydroquinolinyl, tetra Hydroquinolinyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, benzocyclobutyl, Sulfhydryl, decyl. The above aromatic ring, aromatic heterocyclic ring or fused aromatic ring group may be independently substituted by 0-5 R ⁴ groups;

( 6 ) C Ci。环烷基或环烯基，所述基团可部分或全部被卤代，或选择性被 1- 3个(^- C₆烷基或 (^- ₆烷基取代； (6) C Ci. a cycloalkyl or cycloalkenyl group, said group being partially or fully halogenated, or optionally substituted by 1 - 3 (^-C ₆ alkyl or (^ _-6 alkyl);

( 7 ) d- 。直链或支链烷基，所述烷基可部分或全部被卤代； (7) d-. a linear or branched alkyl group which may be partially or fully halogenated;

( 8 ) NH -, R³NH-， R³ ₂N-， R³NCO-R³CONH-, R³C00- , R³0C0 -， R³S (0) _m, R³S (0) _BNH, R³NHS (0) - ； (8) NH -, R ³ NH-, R ³ ₂ N-, R ³ NCO-R ³ CONH-, R ³ C00- , R ³ 0C0 -, R ³ S (0) _m , R ³ S (0) _B NH, R ³ NHS (0) - ;

R³独立的为 R ³ independent is

氢原子， d- C₆直链或支链烷基， d- c₆直链或支链烯基，苯基, 萘基，单或双 -0；₄烷基氨基 d-Cs烷基； m为 0， 1或 2; a hydrogen atom, d-C ₆ linear or branched alkyl, d-c ₆ straight or branched alkenyl, phenyl, naphthyl, mono or di-O; ₄ alkylamino d-Cs alkyl; m Is 0, 1 or 2;

R⁴独立的为 R ⁴ independent is

c) 卤素，硝基，羧基， d-C₆直链或支链烷基， d-C₆直链或支链烯基， CH^。环烷基， 0₅-(：₈环烯基，羟基，腈基， Cf~C₆直链或支链垸氧基，三氟甲基，三氟甲氧基； c) halogen, nitro, carboxy, dC ₆ straight or branched alkyl, dC ₆ straight or branched alkenyl, CH^. Cycloalkyl, 0 ₅ -(: ₈ cycloalkenyl, hydroxy, nitrile, Cf~C ₆ straight or branched decyloxy, trifluoromethyl, trifluoromethoxy;

NH₂-, R³NH-， R³ ₂N -， R³NC0 - R³C0NH -， R³C00 -， R³0C0-, R³S (0) _a, R³S (0) _mNH, R³NHS (0) _m -。 NH ₂ -, R ³ NH-, R ³ ₂ N -, R ³ NC0 - R ³ C0NH -, R ³ C00 -, R ³ 0C0-, R ³ S (0) _a , R ³ S (0) _m NH , R ³ NHS (0) _m -.

2. 权利要求 1的化合物，其中： 2. The compound of claim 1 wherein:

！^为苯基，吡唑基，咪唑基，喁唑基，异喁唑基，噻唑基，异噻唑基，吡咯基，苯并咪唾基，呋喃基，噻吩基，吡喃基，萘基，噻唑基，嘌呤基，喹啉基，嘧啶基。 ! ^ is phenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, benzopyranyl, furyl, thienyl, pyranyl, naphthyl, Thiazolyl, fluorenyl, quinolinyl, pyrimidinyl.

3. 权利要求 2的化合物，其中： 3. The compound of claim 2, wherein:

Ar₂为苯并吡喃基，苯并二氢吡喃基，苯并吡喃酮基，苯并哒嗪基，苯并嘧啶基，苯并吡嗪基，苯并哌啶基，苯并噻唑基，苯并噁唑基，苯并异喁唑基，苯并吡唑基，苯并异噻唑基，苯并三氮唑基， 1， 3 苯并间二氧杂环基。 Ar ₂ is benzopyranyl, benzopyranyl, benzopyranone, benzoxazinyl, benzopyrimidinyl, benzopyrazinyl, benzopiperidinyl, benzothiazole Benzo, benzoxazolyl, benzisoxazolyl, benzopyrazolyl, benzisothiazolyl, benzotrien Azazolyl, 1, 3 benzodioxanyl.

4. 权利要求 3的化合物，其中： 4. The compound of claim 3, wherein:

L独立的为 L independent

( 2 ) d- C₄饱和或不饱和的，直链或支链碳链；其中的一到多个亚甲基独立的被 0， NH, S ( 0 ) _ra或者 0-2个羰基所替代；并且所述联接基团可被一到多个卤原子取代； m为 0， 1或 2。 ( 2 ) d-C ₄ saturated or unsaturated, linear or branched carbon chain; one or more methylene groups of which are independently replaced by 0, NH, S ( 0 ) _ra or 0-2 carbonyl groups And the linking group may be substituted by one or more halogen atoms; m is 0, 1 or 2.

5. 权利要求 1-4任一项的化合物，其选自： 5. A compound according to any one of claims 1 to 4 which is selected from the group consisting of:

1 - [3-叔丁基 -1- (4 -甲基苯基） -1H-5-吡唑基] -3- [8- (3， 4 -二氢- ⁵-甲氧基 -² 色烯基）〗脲 1-[3-tert-Butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-[8-(3,4-dihydro- ⁵ -methoxy- ² color Alkenyl)

1- [3-叔丁基 -1- (4-氯苯基） -1 5-吡唑基] -3- [8 （5-甲氧基 1-[3-tert-Butyl-1-(4-chlorophenyl)-1 5-pyrazolyl]-3-[8 (5-methoxy)

- 2 色烯基）]脲 - 2-color alkenyl)]urea

1- [3-叔丁基 - 1- (4 -甲基苯基） - 1H- 5 -吡唑基] -3- [8- (5-甲氧基 -2^色烯基)〗脲 1-[3-tert-butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-[8-(5-methoxy-2^chromenyl)-urea

1- [3-叔丁基 -1- (4-甲基苯基） -1H-5-吡唑基] -3- {5- {8- [2- (⁴_***啉基）乙酰氨基] - ² 色烯基脲 1-[3-tert-Butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{5- {8- [2-( ⁴ _ morphinolinyl)acetamido] - ^2- color alkenyl urea

1 - [3-叔丁基 -1 -苯基 -1^·5-吡唑基] -3- [8- (3 , 4-二氢 -5-甲氧基 -2 色烯基）]脲 1-[3-tert-butyl-1-phenyl-1^.5-pyrazolyl]-3-[8-(3,4-dihydro-5-methoxy-2-chromenyl)]urea

1 - [3-叔丁基 -1- (4 甲基苯基) -1H- 5-吡唑基] -3- {8- {3， 4 -二氢- 5- [2- (4-***啉基)乙氧基] -2^色烯基 } }脲 1-[3-tert-Butyl-1-(4-methylphenyl)-1H- 5-pyrazolyl]-3-{8- {3,4-dihydro-5-[2-(4-morphine) Phenyl)ethoxy] -2^-alkenyl} }Urea

1- [3-叔丁基 -1- (4-甲基苯基） -1Η-5-吡唑基〗 -3- [8- (5-硝基 1-[3-tert-Butyl-1-(4-methylphenyl)-1Η-5-pyrazolyl]-3-[8-(5-nitro

- 2^ "色烯基）]脲 - 2^ "Alkenyl"]urea

1 - [3-叔丁基 -1-苯基 -1^5-吡唑基 ] -3- {8- {3 , 4-二氢 -5- [2- (4-***啉基）乙氧基] -2^色烯基 } }脲 1-[3-tert-Butyl-1-phenyl-1^5-pyrazolyl]-3-{8- {3,4-dihydro-5-[2-(4-morphinolinyl)ethoxylate Base] -2^色烯}}Urea

1- [3-叔丁基 -1- (4 -氟苯基） -li?~5-吡唑基] -3- {8- {3, 4-二氢一 ⁵_[₂-₍₄—***啉基）乙氧基] -2^色烯基 }}脲 1-[3-tert-Butyl-1-(4-fluorophenyl)-li?~5-pyrazolyl]-3-{8- {3, 4-dihydrogen a ⁵ _[ ₂ - ₍₄ - morphinolinyl)ethoxy] -2^-alkenyl}}urea

1- [3-叔丁基 -1- (4-氯苯基） -1^·5-吡唑基] -3- {8- {3, 4-二氢 -5- [2- (⁴-***啉基）乙氧基] -2^·色烯基 }}脲 1-[3-tert-Butyl-1-(4-chlorophenyl)-1(5-pyrazolyl)-3-(8-{3,4-dihydro-5-[2-( ^4- Morpholine)ethoxy]-2^·alkenyl}}urea

1- [3-叔丁基 -1- (4-溴苯基) -1^5 -吡唑基] -3- {8- {3， 4 -二氢 -5-〖2 - (4-***啉基）乙氧基] -2^色烯基 }}脲 1-[3-tert-Butyl-1-(4-bromophenyl)-1(5-pyrazolyl)-3-(8-{3,4-dihydro-5-[2-(4-morphine) Phenyl)ethoxy]-2^enyl}}urea

1- [3-叔丁基 -1- (4-甲氧基苯基) - 1^·5-吡唑基] -3- {8- {3, 4 - 二氢 -5- [2- (4-***啉基）乙氧基] -2^·色烯基 }}脲 1-[3-tert-Butyl-1-(4-methoxyphenyl)-1 ^·5-pyrazolyl]-3-{8- {3, 4 - dihydro-5- [2- ( 4-morphocolinyl)ethoxy] -2^·chromenyl}}urea

1-[3-叔丁基 - 1-(4-氨基磺酰基苯基）-1 5-吡唑基] -3-{8-{3， 4-二氢 -5- [2- (4-***啉基）乙氧基] -2^·色烯基 }} 脲 1-[3-tert-butyl-1-(4-aminosulfonylphenyl)-1 5-pyrazolyl]-3-{8-{3,4-dihydro-5- [2- (4- Morpholine) Ethoxy] -2^·Alkenyl}} Urea

1 - [3-叔丁基 - 1- (4-硝基苯基） -1^"5-吡唑基] -3- {8- {3, 4-二氢 -5 -〖2- (4-***啉基）乙氧基] 色烯基 }}脲 1-[3-tert-butyl- 1-(4-nitrophenyl)-1^"5-pyrazolyl]-3-{8- {3, 4-dihydro-5 -〖2- (4 -morpholinyl)ethoxy]chromenyl}}urea

1- [3-叔丁基 - 1- (4-甲基苯基） -1H-5-吡唑基〗 -3- {8-[3, 4 -二氢一 ₅- (4-***啉基酰基甲氧基) -2^·色烯基] }脲 1-[3-tert-butyl-1-(4-methylphenyl)-1H-5-pyrazolyl-3-(8-[3,4-dihydro- _5- (4-morphinolinyl) Acylmethoxy) -2^·chromenyl] }urea

1 -（3-叔丁基 -5-异喁唑基） -3- {8- {3， 4-二氢 -5- [2- (4-*** 啉基）乙氧基] -2^~色烯基 }}脲 1-(3-tert-butyl-5-isoxazolyl)-3-{8- {3,4-dihydro-5-[2-(4-morphinolinyl)ethoxy]-2^~ Alkenyl}}urea

1- (5 -叔丁基- 3-异噁唑基） -3- {8- {3 , 4 -二氢 -5 - [2- (4-*** 啉基）乙氧基] -²^"色烯基脲 1-(5-tert-butyl-3-isoxazolyl)-3-{8- {3 , 4 -dihydro-5 - [2-(4-morphinolinyl)ethoxy] - ² ^" Color alkenyl urea

1 - [1 -叔丁基- 3- (4-甲基苯基) -1^·4-吡唑基〗 -3- {8- {3, 4 -二氢一 ⁵— [²一(⁴一***啉基）乙氧基〗 -²^色烯基 }}脲 1-[1-tert-butyl-3-(4-methylphenyl)-1(4-pyrazolyl)-3-(8-{3,4-dihydro- ^5- [ ^2] ( ⁴ Monomorpholine)ethoxy ² - ² ^-alkenyl}}urea

1- [4-叔丁基 -1- (4-甲基苯基） -l?"2 -咪唑基] -3- {8- {3， 4-二氢一 ₅一〖₂一（₄一***啉基）乙氧基] -2 色烯基 }}脲 1- [4-tert-Butyl-1- (4-methylphenyl) -l "2 -? Imidazol-yl] -3- {8- {3, _{4-dihydro-2-one} _{_5-〖(4} a Morpholinyl)ethoxy] -2 alkenyl}}urea

1- [3-叔丁基 -1- (4-甲基苯基) -1H-5-吡唑基] -3- {8- {3, 4-二氢 -5- [2- (4-吡啶基)氧基乙氧基〗 -2^·色烯基脲 1-[3-tert-Butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{8- {3, 4-dihydro-5- [2- (4- Pyridyl)oxyethoxy]-2^·enyl urea

' 1- [3 -叔丁基- 1-(4-甲基苯基) -1H-5-吡唑基] - 3-{8-{3, 4-二氢一 ⁵— {²一[⁴— (顺式一², 6-二甲基） ***啉基〗乙氧基 } -²^"色烯基 "脲 1- [3-叔丁基- 1- (4-甲基苯基) - 1H-5-吡唑基] -3- {8- {3, 4-二氢 -5-U-(l-咪唑基）乙氧基] -2^色烯基 }}脲 ' 1- [3 - tert-butyl 1-(4-methylphenyl) -1H-5-pyrazolyl] - 3-{8-{3, 4-dihydro- ^5- { ² a[ ⁴ - ^(cis-2, 6-dimethyl) morpholino-yl} ethoxy〗 - ^ ² "color alkenyl" urea 1-[3-tert-butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{8- {3, 4-dihydro-5-U-(l-imidazole Ethyloxy] -2^-alkenyl}}urea

1- [3-叔丁基 -1- (4-甲基苯基) -1H-5-吡唑基〗 -3- {8- {3, 4 -二氢 -5 - [2-(1-1， 2, 4 -三氮唑基）乙氧基] - 2 色烯基 }}脲 1-[3-tert-Butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{8- {3,4-dihydro-5-[2-(1- 1, 2, 4 -triazolyl)ethoxy] - 2 alkenyl}}urea

1- [3-叔丁基 -1- (4-氯苯基) -1^5-吡唑基] -3- {8- {3， 4-二氢 -5- {2- [4- (顺式 -2， 6-二甲基）***啉基]乙氧基 } -²^色烯基 }} 脲 1-[3-tert-Butyl-1-(4-chlorophenyl)-1^5-pyrazolyl]-3-{8- {3, 4-dihydro-5- {2- [4- ( Cis-2,6-dimethyl)morphinolinyl]ethoxy} - ² ^-alkenyl}} Urea

1- [3-叔丁基 -1- (3, 4-二甲基苯基） -1^5-吡唑基] -3- {8- {3, 4 -二氢 -5- [2- (4-***啉基）乙氧基] -2^色烯基 }}脲 1-[3-tert-Butyl-1-(3,4-dimethylphenyl)-1^5-pyrazolyl]-3-{8- {3, 4-dihydro-5- [2- (4-morphinolinyl)ethoxy] -2^-alkenyl}}urea

1- [3-叔丁基 -1- (3， 4-二氯苯基） - 1^5-吡唑基] -3 - {8- {3， 4 -二氢 -5-〖2- (4-***啉基）乙氧基] -2^色烯基 }}脲 1-[3-tert-Butyl-1-(3,4-dichlorophenyl)-1 ^5-pyrazolyl] -3 - {8- {3, 4-dihydro-5-〖2- 4-morphocolinyl)ethoxy] -2^-alkenyl}}urea

1- [3 -叔丁基- 1- (3-甲基苯基） -1^5-吡唑基] -3- {8- {3, 4-二氢 -5- [2- (4-***啉基）乙氧基] - 2 色烯基 }}脲 1-[3-tert-butyl-1-(3-methylphenyl)-1^5-pyrazolyl]-3-{8- {3, 4-dihydro-5- [2- (4- Morpholinyl)ethoxy]-2 alkenyl}}urea

1 - [ (3-叔丁基 -1-萘基） -1 5-吡唑基] -3- {8- {3， 4-二氢 -5-[²-(⁴-***啉基）乙氧基] -²^"色烯基 }}脲 1-[(3-tert-Butyl-1-naphthyl)-1] 5-pyrazolyl]-3-{8- {3,4-dihydro-5-[ ² -( ⁴ -morphinolinyl) Oxy] - ² ^" alkenyl}} urea

1- [3-叔丁基 -1-（4-甲基苯基） -1H-5 -吡唑基] -3- {8- {3, 4-二氢- 5- [2- (1-吡唑基）乙氧基] -2^·色烯基 }}脲 1-[3-tert-Butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{8- {3, 4-dihydro- 5- [2- (1- Pyrazolyl)ethoxy] -2^·alkenyl}}urea

1- [3-叔丁基 -1- (4-甲基苯基） -1H-5-吡唑基] -3- {8- {3, 4-二氳- 5- [2- (1-哌啶 -4-酮基）乙氧基] - 2 色烯基 }}脲 1-[3-tert-Butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{8- {3, 4-diindole-5- [2- (1- Piperidin-4-one)ethoxy]-2 alkenyl}}urea

1- [3-叔丁基 -1- (4-甲基苯基） -1H-5-吡唑基] -3- {8- {3， 4 -二氢 -5-[2- (4-***啉基）乙酰氨基] -2¥"色烯基 }}脲 1-[3-tert-Butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{8- {3, 4-dihydro-5-[2- (4- Morpholinyl)acetamido] -2¥"color alkenyl}}urea

1- [3-叔丁基 -1- (4-三氟甲基苯基) -1^-5-吡唑基] -3- {8- {3, 4-二氢 -5- [2- (4-***啉基）乙氧基〗 -²^色烯基 }}脲 1-[3-tert-Butyl-1-(4-trifluoromethylphenyl)-1^-5-pyrazolyl]-3-{8- {3, 4-dihydro-5- [2- (4-morphinolinyl)ethoxy] - ² ^color alkenyl}}urea

1-[3-叔丁基 -1-(4-乙基苯基） -1^5-吡唑基 ]-3- {8-{3， 4 -二氢- 5- [2- (4-***啉基）乙氧基] -2^·色烯基 }}脲 - 1-[3-tert-Butyl-1-(4-ethylphenyl)-1^5-pyrazolyl]-3-{8-{3,4-dihydro-5-[2-(4- Morpholine) Ethoxy] -2^·Alkenyl}} Urea

1- [ 3-叔丁基 -1- (4-叔丁基苯基） -1 ^"5-吡唑基] -3- {8- {3 , 4- 二氢- 5- [2- (4-***啉基）乙氧基] -2^色烯基 }}脲 1- [3 -叔丁基" 4- (4-三氟甲基苯基) -1^-5 -吡唑基] -3- {8- {3 , 4-二氢- 5- [2- (1-咪唑基）乙氧基] - 2^色烯基 } }脲 1-[ 3-tert-Butyl-1-(4-tert-butylphenyl)-1^"5-pyrazolyl]-3-{8- {3, 4-dihydro- 5- [2- ( 4-morphocolinyl)ethoxy] -2^-alkenyl}}urea 1-[3-tert-butyl" 4-(4-trifluoromethylphenyl)-1^-5-pyrazolyl]-3-{8- {3, 4-dihydro-5-[2- (1-imidazolyl)ethoxy]-2^enyl}}urea

1- [3- 叔丁基 -1- (4- 甲基苯基）- 1H-5 - 吡唑基] 3 - {8- {5 - [2- (4-***啉基）乙氧基] 色烯基 H脲 1-[3-tert-Butyl-1-(4-methylphenyl)-1H-5-pyrazolyl] 3 - {8- {5 - [2- (4-morphinolinyl)ethoxy] Alkenyl Hurea

1 - [3-叔丁基 -1- (4 -甲基苯基) - 1H-5 -吡唑基] -3- {8- {3, 4 -二氢- 5- [2- (4-吡啶基）乙氧基] 色烯基 } }脲 1-[3-tert-Butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{8- {3,4-dihydro-5-[2- (4- Pyridyl)ethoxy]chromenyl}}urea

1- [3 -叔丁基- 1- (4 腈基苯基) -1^-'5-吡唑基] -3- {8- {3 , 4-二氢- 5- [2- (4-***啉基）乙氧基] - 2 色烯基 } }脲 1-[3-tert-butyl-1-(4-cyanophenyl)-1^-'5-pyrazolyl]-3-{8- {3, 4-dihydro- 5- [2- (4 -morpholinyl)ethoxy]-2 alkenyl} }urea

1- [3-叔丁基 -1- (3 -氯- 4-氟苯基） -1 5 -吡唑基] -3- {8- {3， 4-二氢- 5- [2 -（4-***啉基）乙氧基] -2^色烯基 } }脲 1-[3-tert-Butyl-1-(3-chloro-4-fluorophenyl)-1 -pyrazolyl]-3-{8- {3, 4-dihydro-5-[2-(( 4-morpholinyl)ethoxy]-2^-alkenyl} }urea

1- [3-叔丁基- 1- (4-甲基苯基) -1H-5-吡唑基] -3- {8- {5- [ (4 - 甲氧基苯基）甲氧基] - 色烯基 } }脲 1-[3-tert-butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-{8- {5-[(4-methoxyphenyl)methoxy ] - Alkenyl} } Urea

1- [3-叔丁基 -1- (4-甲基苯基） -1H-5-吡唑基] - 3- {8- [5- (4- ***啉基酰基甲氧基) -2 ^色烯基] }脲 1-[3-tert-Butyl-1-(4-methylphenyl)-1H-5-pyrazolyl]-3-(8-[5-(4-morphinolinyl methoxymethoxy)-2 ^色烯]]Urea

1- [3-叔丁基 - 1- (4-氟苯基） - li¥~5-吡唑基 ] -3- {8- {5- [2- (4- ***啉基）乙氧基] - 2^色烯基 } }脲 1-[3-tert-butyl-1-(4-fluorophenyl)-li¥~5-pyrazolyl]-3-{8- {5- [2-(4-morphinolinyl)ethoxy ] - 2^色基}}Urea

1- [3 -叔丁基- 1-（4-氯苯基） -1^5 -吡唑基] - 3- {8- {5- [2- (4- ***啉基）乙氧基〗 -2^色烯基脲 1-[3-tert-butyl-1-(4-chlorophenyl)-1(5-pyrazolyl)-3-(8-{5-[5-[2-(4-morphinolinyl)ethoxy] -2^color alkenyl urea

1- [3-叔丁基 -1- (4-溴苯基） -1^5-吡唑基] -3- {8- {5- [2- (4- ***啉基）乙氧基] -2^·色烯基 } }脲 1-[3-tert-Butyl-1-(4-bromophenyl)-1^5-pyrazolyl]-3-{8- {5- [2-(4-morphinolinyl)ethoxy] -2^·Alkenyl} }Urea

1 -（ 3-叔丁基 1-苯基 -1^5-吡唑基） -3- {8- {5- [2- (4-*** 啉基）乙氧基] -2 色烯基 } }脲 1-(3-tert-butyl 1-phenyl-1^5-pyrazolyl)-3-{8-{5- [2-(4-morphinolinyl)ethoxy]-2 alkenyl} Urea

1- [3- 叔丁基 - 1- (4- 甲氧基苯基）-1 5- 吡唑基] -³- {⁸- {5- [² -（⁴-***啉基）乙氧基] ²^色烯基 } }脲 1-[3-tert-Butyl- 1-(4-methoxyphenyl)-1 5-pyrazolyl] - ³ - { ⁸ - {5- [ ² -( ⁴ -morphinolinyl)ethoxy ² ^色基}}Urea

1- [3-叔'丁基 -1- (4-三氟甲基苯基 -1 & ·5- 吡唑 ] -3- {8- { [²- (⁴-***啉基）乙氧基] -2 ?"色烯基 } }脲 1-[3-tert-Butyl-1-(4-trifluoromethylphenyl-1 & 5-pyrazole]-3-{8- { [ ² - ( ⁴ -morphinolinyl)ethoxy ] -2 ?"Alkenyl}}Urea

1 - [3- 叔丁基 -1- (4- 硝基苯基）-1^5- 吡唑基] -3- {8- {5- [2- (⁴-***啉基）乙氧基] - ² 色烯基} }脲 1 - [3-tert-butyl-1-(4-nitrophenyl)-1^5-pyrazole ] {-3-{8- {5- [2-( ⁴ -morphinolinyl)ethoxy] - ² - alkenyl} }

1-[3- 叔丁基 - 1- (4- 腈基苯基）- 1 5- 吡唑基] -3- {8- {5- [2- (4-***啉基）乙氧基] - ²^色烯基 }}脲 1-[3-tert-butyl-1-(4-cyanophenyl)-1 5-pyrazolyl]-3-{8-{5-[2-(4-morphinolinyl)ethoxy] - ² ^Color alkenyl}}urea

1-C3- 叔丁基 - 1-(4- 甲基苯基）-1Η-5- 吡唑基] -3- {8- {5- [2- (1-1， 2, 4 -三氮唑基）乙氧基 ]- 色烯基 }}脲 1-C3-tert-butyl-l-(4-methylphenyl)-1Η-5-pyrazolyl]-3-{8- {5- [2-(1-1, 2, 4 - trinitro) Azyl)ethoxy]-chromenyl}}urea

1-[3- 叔丁基 -1-(4- 乙基苯基）-1^~5- 吡唑基 ]-3- {8- {5- [2- (4-***啉基）乙氧基] -²^色烯基 }}脲 1-[3-tert-Butyl-1-(4-ethylphenyl)-1^~5-pyrazolyl]-3-{8- {5- [2-(4-morphinolinyl)ethoxylate Base] - ² ^ color alkenyl}} urea

1-[3- 叔丁基 -1- (4- 叔丁基苯基）-1^5- 吡唑基] 3- {8- {5- [2 -（4-***啉基）乙氧基] -2 色烯基 }}脲 1-[3-tert-Butyl-1-(4-tert-butylphenyl)-1^5-pyrazolyl] 3-{8- {5- [2-(4-morphinolinyl)ethoxylate ] -2 alkenyl}}urea

1-[3- 叔丁基 -1- (3- 氯 -4- 氟苯基）- 1^~5- 吡唑基] -3- {8- {5- [2- (4-***啉基）乙氧基] 2^·色烯基 } }脲 1-[3-tert-Butyl-1-(3-chloro-4-fluorophenyl)- 1^~5-pyrazolyl]-3-{8- {5- [2-(4-morphinolinyl) Ethoxy] 2^·enyl alkenyl} }urea

1-[3-叔丁基 -1-(3 ， 4-二甲基苯基）-1^5-吡唑基]- 3- {8- {5- [2- (4-***啉基）乙氧基〗 -2 色烯基 }}脲 1-[3-tert-Butyl-1-(3,4-dimethylphenyl)-1^5-pyrazolyl]- 3-{8- {5- [2-(4-morphinolinyl) Ethoxyl -2 color alkenyl}}urea

1- [3-叔丁基 -1-(3 ， 4- 二氯苯基）-1^5- 吡唑基]- ³-{8- {⁵-[²-(⁴-***啉基）乙氧基] - ² 色烯基 }}脲 1-[3-tert-Butyl-1-(3,4-dichlorophenyl)-1^5-pyrazolyl]- ³ -{8- { ⁵ -[ ² -( ⁴ -morphinolinyl) Oxy] ^-2 -alkenyl}}urea

1 -（3-叔丁基 -5-异喁唑基） -3- {8- {5- [2 (4-***啉基）乙氧基] - ² 色烯基 }}脲 1-(3-tert-butyl-5-isoxazolyl)-3-{8-{5-[2 (4-morphinolinyl)ethoxy] ^-2 -isopropenyl}}urea

1- (5-叔丁基 -3-异噁唑基） -3- {8- {5- [2- (4 -***啉基）乙氧基] - 2^色烯基 }}脲 1-(5-tert-Butyl-3-isoxazolyl)-3-{8- {5- [2-(4- morphinyl)ethoxy]- 2^-alkenyl}}urea

叔丁基 -3- (4- 甲基苯基）-li¾M- 吡唑基] -³ - {⁸-{⁵ - [2-(⁴ -***啉基）乙氧基] -2^色烯基 }}脲 tert-Butyl-3-(4-methylphenyl)-li3⁄4M-pyrazolyl] - ³ - { ⁸ -{ ⁵ - [2-( ⁴ -morphinolinyl)ethoxy] -2^ }}urea

1-[3- 叔丁基 -1- (3- 甲基苯基）- 1^~5- 吡唑基]-3-{8-{5-[²-(4-***啉基）乙氧基] - 2^色烯基 }}脲 1-[3-tert-Butyl-1-(3-methylphenyl)- 1^~5-pyrazolyl]-3-{8-{5-[ ² -(4-morphinolinyl)ethoxylate Base] - 2^color alkenyl}}urea

1- [ (3-叔丁基 -1-萘基） -1^-5-吡唑基] -3- {8- {5- [2- (4-*** 啉基）乙氧基] -25~色烯基 }}脲 1-[(3-tert-Butyl-1-naphthyl)-1^-5-pyrazolyl]-3-{8-{5-[2-(4-morphinolinyl)ethoxy]-25 ~Color alkenyl}}urea

1-E4- 叔丁基 -1- (4- 甲基苯基）-1^~2- 咪唑基]-³-{⁸-{⁵-[²_(⁴-***啉基）乙氧基] - ²^色烯基 H脲 l-[3- 叔丁基 - 1-(4- 甲基苯基）-1Η 5- 吡唑基]-3-{8-{5-{2-[4-（顺式-2,6-二甲基）***淋基〗乙氧基 } -2ff- 色烯基 }}脲 1-E4-tert-butyl-1-(4-methylphenyl)-1^~2-imidazolyl]- ³ -{ ⁸ -{ ⁵ -[ ² _( ⁴ -morphinolinyl)ethoxy] - ² ^Color alkenyl Hurea L-[3-tert-butyl-1-(4-methylphenyl)-1Η 5-pyrazolyl]-3-{8-{5-{2-[4-(cis-2,6- Dimethyl)morphine lysine ethoxylate} -2ff-chromenyl}}urea

以及其可药用 Jk或溶剂化物。 And its pharmaceutically acceptable Jk or solvate.

6. 制备权利要求 1-5任一项所述化合物的方法，该方法包括下式的化合物： o 6. A process for the preparation of a compound according to any one of claims 1 to 5, which comprises a compound of the formula: o

Ar₁ H"^OR₆ Ar ₁ H"^OR ₆

(A) (A)

与 P- L-Ar ₂-冊₂在合适的溶剂，合适的碱中于 100°C反应 1 小时到 120小时得到式 I的化合物, 其中， Α^Α^,Ι^Ρ的定义同通式 I， R^fi为三氯甲基，对硝基苯基，乙氧基，咪唑基， ***基等。 The compound of the formula I can be obtained by reacting P-L-Ar ₂ - ₂ in a suitable solvent in a suitable base at 100 ° C for 1 hour to 120 hours, wherein Α^Α^, Ι^Ρ is defined by the same formula. I, R ^fi is trichloromethyl, p-nitrophenyl, ethoxy, imidazolyl, triazolyl and the like.

7. 权利要求 6所述的方法，其中所迷式（A)化合物制备如下：使下式的化合物： 7. The method of claim 6, wherein the compound of formula (A) is prepared as follows: a compound of the formula:

X o X o

R_eO^OR₆ R _e O^OR ₆

与 Α_ΓιΝΗ₂在合适的溶剂，合适的碱中于- 15 -25 Ό反应 10分钟到 24小时得到式（A)的化合物，其中， A 的定义同通式 I, R⁶为三氯甲基，对硝基苯基，乙氧基，咪唑基， ***基等。 The compound of the formula (A) is obtained by reacting with Α _Γι ΝΗ ₂ in a suitable solvent in a suitable base at - 15 -25 Torr for 10 minutes to 24 hours, wherein A is as defined in the formula I, and R ⁶ is trichloromethane. Base, p-nitrophenyl, ethoxy, imidazolyl, triazolyl and the like.

8. 制备权利要求 1-5任一项所述化合物的方法，该方法包括下式的化合物：

8. A process for the preparation of a compound according to any one of claims 1 to 5 which comprises a compound of the formula:

(B) (B)

与 Α_ΓιΝΗ₂在合适的溶剂，合适的碱中于反应 1小时到 120小时得到式 I的化合物，其中， ^ ^^，？的定义同通式^ R⁶ 为三氯甲基，对硝基苯基，乙氧基，咪唑基， ***基等。 The compound of formula I is obtained by reacting with Α _Γι ΝΗ ₂ in a suitable solvent in a suitable base for from 1 hour to 120 hours, wherein ^ ^^,? The definition of the same formula ^ R ⁶ is trichloromethyl, p-nitrophenyl, ethoxy, imidazolyl, triazolyl and the like.

9. 权利要求 6所述的方法，其中所述式（Β)化合物制备如下: 使下式的化合物：

9. The method of claim 6, wherein the compound of the formula (Β) is prepared as follows: A compound of the formula:

与 P- L-Ar₂-冊₂在合适的溶剂，合适的碱中于" -15 Ό -25 °C反应 10分钟到 24小时得到式（B)的化合物。其中， Ar₂, L，P的定义同通式 I， R⁶为三氯甲基，对硝基苯基，乙氧基，咪唑基， ***基等。 The compound of the formula (B) can be obtained by reacting with P-L-Ar ₂ - ₂ in a suitable solvent in a suitable base at "-15 Ό -25 ° C for 10 minutes to 24 hours. Among them, Ar ₂ , L, P The definition is the same as the formula I, R ⁶ is trichloromethyl, p-nitrophenyl, ethoxy, imidazolyl, triazolyl and the like.

10. 药用组合物，其含有权利要求 1 - 5中任一项的化合物，其可药用盐或溶剂化物以及至少一种药学上可接受的载体、稀释剂或赋形剂。 A pharmaceutical composition comprising a compound according to any one of claims 1 to 5, a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable carrier, diluent or excipient.

11. 权利要求 1-5 中任一项的化合物用于制备治疗细胞因子 ( TNF- α , IL- 1等）介导的疾病，危险因子或病症的药物的用途。 11. Use of a compound according to any one of claims 1 to 5 for the manufacture of a medicament for the treatment of a cytokine (TNF-α, IL-1, etc.) mediated disease, a risk factor or a condition.

12. 权利要求 8的用途，其中所述疾病、危险因子或病症为牛皮癣性关节炎，莱特尔氏综合征，痛风，外伤性关节炎，风疹性关节炎，急性滑膜炎，类风湿性关节炎，类风湿性脊推炎，骨关节炎，痛风性关节炎及其它关节病，败血症，脓毒性休克，内毒素性休克，革兰氏阴性，败血症，中毒性休克综合征，脑型疟，脑膜炎，局部缺血性中风和出血性中风，神经外伤 /闭合性颅脑损伤，哮喘，成人呼吸窘迫综合症，慢性肺炎，慢性阻塞性肺病，矽肺，肺肉瘤病，骨吸收病，骨质疏松，再狭窄，心脏及脑和肾再灌注损伤，充血性心力衰竭，冠状动脉旁路搭桥 (CABG)术，血检形成，肾小球性肾炎，慢性肾衰竭，糖尿病，糖尿病性视网膜病，黄斑变性，移植物抗宿主反应，同种移植物排斥，炎性肠疾病，节段性回肠炎，溃疡性结肠炎神经变性疾病，肌肉退化，糖尿病性视网膜病，黄斑变性，肿瘤生长和转移，血管生成疾病，流感引起的肺炎，湿疹，接触性皮炎，牛皮癣，晒伤或结膜炎等。 12. The use according to claim 8, wherein the disease, risk factor or condition is psoriatic arthritis, Lyttle syndrome, gout, traumatic arthritis, rubella arthritis, acute synovitis, rheumatoid joint Inflammation, rheumatoid spinal inflammation, osteoarthritis, gouty arthritis and other joint diseases, sepsis, septic shock, endotoxic shock, Gram-negative, sepsis, toxic shock syndrome, cerebral malaria, Brain Membrane inflammation, ischemic stroke and hemorrhagic stroke, neurological trauma/closed craniocerebral injury, asthma, adult respiratory distress syndrome, chronic pneumonia, chronic obstructive pulmonary disease, silicosis, pulmonary sarcoma, bone resorption, bone Loose, restenosis, heart and brain and kidney reperfusion injury, congestive heart failure, coronary artery bypass grafting (CABG), blood test, glomerulonephritis, chronic renal failure, diabetes, diabetic retinopathy, Macular degeneration, graft versus host response, allograft rejection, inflammatory bowel disease, Crohn's disease, ulcerative colitis neurodegenerative disease, muscle degeneration, diabetic retinopathy, macular degeneration, tumor growth and metastasis, Angiogenic diseases, flu-induced pneumonia, eczema, contact dermatitis, psoriasis, sunburn or conjunctivitis.

13. 权利要求 1 一 5中任一项的化合物用于制备抑制 ρ38蛋白激酶药物的用途。 13. Use of a compound according to any one of claims 1 to 5 for the manufacture of a medicament for inhibiting ρ38 protein kinase.

14. 治疗或预防细胞因子（TNF- a , IL-1等）介导的疾病、危险因子或病症的方法，包括给予有此需要的对象治疗有效量的权利要求 1-5中任一项的本发明化合物。 14. A method of treating or preventing a cytokine (TNF-a, IL-1, etc.) mediated disease, risk factor or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of any one of claims 1-5 A compound of the invention.